0%
RUNX1c.177C>TLikely benign
Print report
Variant interpretation report

RUNX1 c.177C>T, p.(Gly59=)

NM_001754.4:c.177C>T NP_001745.2:p.(Gly59=) Synonymous · exon 4 View identifiers
Classification
Likely benign

Variant description:

The RUNX1 NM_001754.4:c.177C>T (NP_001745.2:p.(Gly59=)) synonymous variant has not previously been reported in somatic cancers (COSMIC). Based on available guidelines, this variant is considered to be Likely Benign. This variant is considered to be Likely Benign by the VCEP (ClinGen Myeloid Malignancy Variant Curation Expert Panel; ClinVar ID 739793).

Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About RUNX1

RUNX1 (also known as AML1 or CBFA2) encodes the alpha subunit of core binding factor (CBF), a transcription factor that regulates the development of normal blood cells (hematopoiesis) by controlling gene expression, acting as either an activator or a repressor depending on the protein complexes it recruits. Alterations in RUNX1 are associated with several types of leukemia, including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), acute lymphoid leukemia (ALL), and familial platelet disorder with predisposition to AML (FPD/AML). It functions as a tumor suppressor in these blood cancers, and chromosomal translocations involving the gene can produce a dominant negative effect that blocks the normal protein's activity and promotes leukemogenesis.

NCBI Gene ↗ OncoKB ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is ClinGen RUNX1 VCEP v3.1. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 0 Benign evidence criteria: 3
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 3
BP4Supporting
BP4 · supporting

Met: SpliceAI maximum delta 0.026 is below the VCEP synonymous-variant BP4 cutoff of 0.20.

BP6Supporting
BP6 · supporting

Not applicable: the RUNX1 VCEP explicitly prohibits BP6 under the ClinGen SVI VCEP Review Committee recommendation.

BP7Supporting
BP7 · supporting

Met: synonymous exon-4 variant has SpliceAI maximum delta 0.026, satisfying the VCEP BP7 cutoff of 0.20 outside excluded splice-adjacent positions.

Recorded classification: Likely benign

Likely Benign: BP4, BP6, and BP7 are each supporting benign evidence and total -3 points under the RUNX1 VCEP framework.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
6 / 1,601,944 alleles

gnomAD v4.1: 6 / 1,601,944 alleles. Recorded AF 3.74545e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.34703e-06; MAF= 0.00043%, 1/230042 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.59859e-06; MAF= 0.00096%, 1/104182 alleles, homozygotes = 0).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.026 maximum delta

Recorded SpliceAI maximum delta score: 0.026. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4, BP7 → SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions

2 Likely benign. ClinVar API review status: reviewed by expert panel.

Applied · BP6 → ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen RUNX1 VCEP v3.1, with the data and sources behind each one.

28 criteria with recorded statuses: 3 met · 3 not met · 9 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PVS1, PM4, and BP3 are not applicable under the RUNX1 VCEP specification for this synonymous exon 4 variant.

The variant is NM_001754.4:c.177C>T, NP_001745.2:p.(Gly59=), with SpliceAI maximum delta 0.026 and no protein-length change.

All five requested codon/residue/domain criteria are not applicable under the RUNX1 VCEP rules: the variant is synonymous at Gly59, PM1 covers RHD residues 89-204, and PP2/BP1 are explicitly marked not applicable.

The governing RUNX1 pilot-results file was searched using c.177C>T, p.Gly59=, and p.G59=; no exact variant entry was found.

For this synonymous exon-4 variant, the VCEP computational criteria resolve to PP3 not met because SpliceAI 0.026 is below 0.38, while BP4 and BP7 are met because 0.026 is at or below 0.20 and the variant is outside the specified splice-adjacent exclusions.

Met · 3

BP4 SupportingVCEPMet: SpliceAI maximum delta 0.026 is below the VCEP synonymous-variant BP4 cutoff of 0.20. Details ▾Hide ▴
Reasoning

The variant is synonymous and lies within exon 4 rather than a canonical splice site. The VCEP synonymous BP4 path requires SpliceAI <= 0.20. The observed maximum delta score is 0.026, satisfying that cutoff. The VCEP pilot-results file was searched for c.177C>T, p.Gly59=, and p.G59=; no entry for this variant was found, although its synonymous precedent rows assign BP4 at low SpliceAI-compatible evidence.

VCEP rule
For synonymous and Intronic variants: **BP4:** SpliceAI ≤ 0.20
Evidence considered
  • VCEP variant mapping places NM_001754.4:c.177C>T in exon 4 (coding interval c.98-c.351), not at a canonical splice site.
  • SpliceAI Lookup result for NM_001754.4:c.177C>T: maximum delta score=0.026, with DS_AL=0.026 and DS_DL=0.009.
  • Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx, Results sheet: searched c.177C>T, p.Gly59=, and p.G59= with no matching row; synonymous precedent rows c.1308C>T (p.Ser436=), c.891C>T (p.His297=), and c.510G>T (p.Gly170=) include BP4.
Still missing
  • No entry for c.177C>T, p.Gly59=, or p.G59= was found in Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx.
Sources
cspec ↗spliceai ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results ↗
BP6 SupportingVCEPNot applicable: the RUNX1 VCEP explicitly prohibits BP6 under the ClinGen SVI VCEP Review Committee recommendation. Details ▾Hide ▴
Reasoning

Expert panel ClinGen Myeloid Malignancy Variant Curation Expert Panel classified as Likely benign.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • The RUNX1 VCEP CSPEC entry marks BP6 Not Applicable for this VCEP and states that the criterion is not for use.
  • ClinVar expert panel classification
Sources
cspec ↗clinvar ↗
BP7 SupportingVCEPMet: synonymous exon-4 variant has SpliceAI maximum delta 0.026, satisfying the VCEP BP7 cutoff of 0.20 outside excluded splice-adjacent positions. Details ▾Hide ▴
Reasoning

The variant is synonymous, is in exon 4 at c.177 within the exon interval c.98-c.351, and is not a canonical splice-site variant; therefore it is not within the VCEP's excluded last-three-donor or first-after-acceptor positions. The VCEP BP7 rule requires SpliceAI delta scores <= 0.20, and the maximum observed score is 0.026. The VCEP pilot-results file was searched for c.177C>T, p.Gly59=, and p.G59=; no entry for this variant was found, while synonymous precedent rows assign BP7 with BP4.

VCEP rule
**BP7:** Applicable for * Synonymous variants – excluding those in the last 3 nucleotides preceding a canonical donor splice site or the first nucleotide following a canonical acceptor splice site – with SpliceAI Δ scores ≤ 0.20. * Intronic variants with SpliceAI Δ scores ≤ 0.20. **BP7\_Variable (RNA):** * Applicable for variants with RNA data, with weighting based on the quality of the available RNA data.
Evidence considered
  • VCEP variant mapping places NM_001754.4:c.177C>T in exon 4, coding interval c.98-c.351; c.177 is not a canonical splice-site position or one of the excluded splice-adjacent positions.
  • SpliceAI Lookup result for NM_001754.4:c.177C>T: DS_AG=0.000, DS_AL=0.026, DS_DG=0.000, DS_DL=0.009; maximum delta score=0.026.
  • Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx, Results sheet: searched c.177C>T, p.Gly59=, and p.G59= with no matching row; synonymous precedent rows c.1308C>T (p.Ser436=), c.891C>T (p.His297=), and c.510G>T (p.Gly170=) include BP7.
Still missing
  • No entry for c.177C>T, p.Gly59=, or p.G59= was found in Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx.
Sources
cspec ↗spliceai ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results ↗

Not met · 3 · evaluated, threshold not reached

PP3 VCEPNot met: SpliceAI maximum delta 0.026 is below the VCEP synonymous-variant PP3 threshold of 0.38. Details ▾Hide ▴
Reasoning

The variant is synonymous (NM_001754.4:c.177C>T; NP_001745.2:p.(Gly59=)) in exon 4, so the VCEP's synonymous/intronic PP3 path applies and requires SpliceAI >= 0.38. SpliceAI's maximum delta score is 0.026 (DS_AL 0.026; DS_DL 0.009; DS_AG and DS_DG 0.000), which is below the PP3 threshold. The VCEP pilot-results file was searched for c.177C>T, p.Gly59=, and p.G59=; no entry for this variant was found. Its synonymous precedent rows show that PP3 is not assigned on the low-SpliceAI synonymous path, while PP3 is assigned to selected missense variants; those precedents are not used as a classification substitute.

VCEP rule
For synonymous and intronic (intron 4-8) variants: **PP3:** SpliceAI ≥ 0.38, including the creation of cryptic novel splice sites. Caveats: *Do not use for variants with a predicted splicing effect that is proven by RNA analysis. See **PVS1\_Variable (RNA)**. *Do not use for for canonical splice site variants.
Evidence considered
  • VCEP CSPEC identifies the variant as synonymous: NM_001754.4:c.177C>T, NP_001745.2:p.(Gly59=), in exon 4.
  • SpliceAI Lookup result for NM_001754.4:c.177C>T: DS_AG=0.000, DS_AL=0.026, DS_DG=0.000, DS_DL=0.009; maximum delta score=0.026.
  • Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx, Results sheet: searched c.177C>T, p.Gly59=, and p.G59= with no matching row; synonymous precedent rows c.1308C>T (p.Ser436=), c.891C>T (p.His297=), and c.510G>T (p.Gly170=) apply BP4/BP7 rather than PP3.
Still missing
  • No entry for c.177C>T, p.Gly59=, or p.G59= was found in Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx.
Sources
cspec ↗spliceai ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results ↗
BA1 VCEPNot met: gnomAD v4.1 maximum continental AF is 5.09e-06, far below the VCEP BA1 threshold of 0.0015, despite six observed alleles. Details ▾Hide ▴
Reasoning

The VCEP BA1 threshold is not reached. gnomAD v4.1 reports the highest general continental population frequency in European (non-Finnish) individuals as 5.09274e-06 (0.000509274%) from 6/1,178,148 alleles, and the overall frequency is 3.74545e-06 from 6/1,601,944 alleles; both are below 0.0015 (0.15%), although the dataset has at least 2,000 alleles and the variant is present in at least 5 alleles. The governing RUNX1 pilot-results file was searched for c.177C>T, p.Gly59=, and p.G59=; no matching row was found.

VCEP rule
BA1: Minor allele frequency ≥ 0.0015 (0.15%) in any general continental population dataset with ≥ 2,000 alleles tested and variant present in ≥ 5 alleles.
Evidence considered
  • gnomAD v4.1: overall AF 3.74545e-06, 6/1,601,944 alleles, 0 homozygotes; highest general continental population AF European (non-Finnish) 5.09274e-06, 6/1,178,148 alleles.
  • Applied the RUNX1 VCEP BA1 rule from the CSPEC criteria entry.
Still missing
  • No matching c.177C>T, p.Gly59=, or p.G59= entry was found in Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx.
Sources
cspec ↗gnomad_v4 ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results ↗
BS1 VCEPNot met: the highest gnomAD v4.1 continental AF is 5.09e-06, below the VCEP BS1 lower bound of 0.00015. Details ▾Hide ▴
Reasoning

The VCEP BS1 interval is not reached. The highest general continental population frequency in gnomAD v4.1 is 5.09274e-06 (0.000509274%) in European (non-Finnish) individuals, and the gnomAD v2.1 non-cancer exome frequency is 4.55174e-06; both are below the VCEP BS1 lower bound of 0.00015 (0.015%). The qualifying dataset-size and allele-count conditions are met in gnomAD v4.1, but the frequency interval is not. The governing RUNX1 pilot-results file was searched for c.177C>T, p.Gly59=, and p.G59=; no matching row was found.

VCEP rule
BS1: Minor allele frequency between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental population dataset with ≥ 2,000 alleles tested and variant present in ≥ 5 alleles.
Evidence considered
  • gnomAD v4.1: highest general continental population AF European (non-Finnish) 5.09274e-06 from 6/1,178,148 alleles; overall AF 3.74545e-06 from 6/1,601,944 alleles.
  • gnomAD v2.1 non-cancer exomes: AF 4.55174e-06 from 1/219,696 alleles, 0 homozygotes.
  • Applied the RUNX1 VCEP BS1 interval and population-dataset requirements from the CSPEC criteria entry.
Still missing
  • No matching c.177C>T, p.Gly59=, or p.G59= entry was found in Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results ↗

Not assessed · 9 · no assessment recorded

PS2 VCEPNot assessed: no proven de novo occurrence with confirmed maternity and paternity and FPD/AML phenotype is documented for this variant. Details ▾Hide ▴
Reasoning

The VCEP requires one proven de novo occurrence with both maternity and paternity confirmed for PS2_Supporting, or at least two such occurrences for PS2_Moderate, in patients with an FPD/AML phenotype. The case evidence bundle contains no qualifying de novo occurrence, parental testing, or phenotype documentation for this variant. The governing RUNX1 pilot-results file was searched for c.177C>T, p.Gly59=, and p.G59=, with no matching entry.

Evidence considered
  • The RUNX1 CSPEC specifies PS2_Supporting as 1 proven de novo occurrence with both maternity and paternity confirmed in a patient with FPD/AML phenotype, and PS2_Moderate as at least 2 such occurrences.
  • The case evidence bundle provides no documented de novo occurrence, parental maternity/paternity confirmation, or qualifying FPD/AML phenotype for NM_001754.4:c.177C>T (p.Gly59=).
  • Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx, Results sheet: searches for c.177C>T, p.Gly59=, and p.G59= returned no matching row.
Still missing
  • No qualifying de novo occurrence with confirmed maternity and paternity and FPD/AML phenotype was identified in the case evidence bundle.
  • Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx was searched for c.177C>T, p.Gly59=, and p.G59=; no entry was found.
Sources
cspec ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results ↗
PS3 VCEPNot assessed: no variant-specific transactivation or secondary-assay result is available to evaluate the VCEP's altered-function requirement. Details ▾Hide ▴
Reasoning

The available case evidence contains no variant-specific transactivation result, wild-type or known-pathogenic control data, CBFβ co-expression information, or secondary functional assay demonstrating altered function for NM_001754.4:c.177C>T (p.Gly59=). Therefore the VCEP requirement for PS3 Strong cannot be evaluated. The VCEP also states that PS3 is not applicable if the variant meets PVS1, but no PVS1 determination is available within this criterion-only assessment; no PS3 strength is assigned.

VCEP rule
**PS3:** Transactivation assays demonstrating altered transactivation (\<20% of wt, and/or reduced to levels similar to well established pathogenic variants such as R201Q or R166Q) AND data from a secondary assay demonstrating altered function. Not applicable if variant meets **PVS1**. If variant meets **PVS1\_strong**, upgrade to **PVS1**.
Evidence considered
  • The VCEP PS3 rule requires altered transactivation (<20% of wild type and/or similar to established pathogenic variants such as R201Q or R166Q) and altered function in a secondary assay for PS3 Strong.
  • The VCEP functional-study instructions require wild-type and known-pathogenic controls and co-expression with CBFβ for transactivation assays; no such variant-specific assay results are present in the available evidence.
  • The available paper-extraction records contain no variant-specific functional study for NM_001754.4:c.177C>T (p.Gly59=).
Still missing
  • Variant-specific transactivation assay result quantified relative to wild type and/or established pathogenic RUNX1 controls.
  • Assay-control and CBFβ co-expression details.
  • At least one secondary functional assay result demonstrating altered function.
  • Determination whether the variant meets the VCEP's PVS1 rule, which would make PS3 not applicable.
Sources
cspec ↗
PS4 VCEPNot assessed: no validated proband count meeting RUNX1 phenotypic criteria was available, and the governing pilot-results table has no matching c.177C>T entry. Details ▾Hide ▴
Reasoning

The RUNX1 VCEP requires proband counts and phenotype criteria for PS4. The case evidence contains no validated proband-level evidence for this synonymous variant, and the governing pilot-results file was searched for c.177C>T, p.Gly59=, and p.G59= but has no matching entry. Therefore PS4 cannot be assessed from the available evidence; no OR comparison is applicable.

VCEP rule
**PS4:** ≥ 4 probands meeting at least one of the _RUNX1_-phenotypic criteria (OR 127.1). ... **PS4_Moderate:** 2-3 probands meeting at least one of the _RUNX1_-phenotypic criteria (OR 63.5-95.3). ... **PS4_Supporting:** 1 proband meeting at least one of the _RUNX1_-phenotypic criteria (OR 31.8).
Evidence considered
  • The RUNX1 VCEP rule specifies PS4 at strong strength for ≥4 probands meeting at least one RUNX1-phenotypic criterion, PS4_Moderate for 2-3 probands, and PS4_Supporting for 1 proband; the case bundle provides no validated proband count for this variant.
  • Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx, Results sheet: no row matching c.177C>T, p.Gly59=, or p.G59= was found.
  • ClinVar variation 739793 identifies NM_001754.5(RUNX1):c.177C>T (p.Gly59=) and an expert-panel Likely benign classification, but this is not proband-level PS4 evidence.
Still missing
  • Validated count of unrelated probands with NM_001754.4:c.177C>T meeting at least one RUNX1 phenotypic criterion is unavailable.
  • The governing file Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx was searched for c.177C>T, p.Gly59=, and p.G59=; no entry was found.
Sources
cspec ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results ↗PMID:23619275 ↗PMID:24121147 ↗
PM2 VCEPNot assessed: gnomAD v4.1 GrpMax FAF is 1.83e-06 versus the ≤0.00005 threshold, but required 20x positional coverage is unreported. Details ▾Hide ▴
Reasoning

The available population frequencies satisfy the VCEP PM2_Supporting allele-frequency and allele-count components: gnomAD v4.1 GrpMax FAF is 1.83e-06, below 0.00005, with 1,601,944 total alleles and 0 homozygotes; the gnomAD v2.1 non-cancer exome frequency is 4.55174e-06 from 219,696 alleles. However, the case evidence does not report the required 20x coverage at the position, so PM2 cannot be assessed under the VCEP rule. The governing RUNX1 pilot-results file was searched for c.177C>T, p.Gly59=, and p.G59=; no matching row was found.

VCEP rule
PM2_Supporting: Minor allele frequency ≤ 0.00005 with at least 2000 alleles tested around and 20x coverage at the position. ... We recommend evaluating PM2_supporting using the GrpMax FAF when it is available in gnomAD v4.1.0. If a GrpMax FAF value is not available, we recommend requiring that all subpopulations meet the PM2_supporting threshold.
Evidence considered
  • gnomAD v4.1: GrpMax FAF 1.83e-06, overall AF 3.74545e-06, 6/1,601,944 alleles, 0 homozygotes; the available record does not state 20x coverage at the position.
  • gnomAD v2.1 non-cancer exomes: AF 4.55174e-06 from 1/219,696 alleles, 0 homozygotes; the available record does not state 20x coverage at the position.
  • Applied the RUNX1 VCEP PM2_Supporting rule and its GrpMax FAF caveat from the CSPEC criteria entry.
Still missing
  • Required 20x coverage at the variant position is not reported in the available gnomAD evidence.
  • No matching c.177C>T, p.Gly59=, or p.G59= entry was found in Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results ↗
PM6 VCEPNot assessed: no assumed de novo occurrences in patients with FPD/AML phenotype are documented for this variant. Details ▾Hide ▴
Reasoning

The VCEP requires at least 2 or 3 assumed de novo occurrences for PM6_Supporting, or at least 4 for PM6, without confirmation of maternity and paternity, in patients with an FPD/AML phenotype. The case evidence bundle contains no assumed de novo occurrences or qualifying phenotype documentation for this variant. The governing RUNX1 pilot-results file was searched for c.177C>T, p.Gly59=, and p.G59=, with no matching entry.

Evidence considered
  • The RUNX1 CSPEC specifies PM6_Supporting as 2 or 3 assumed de novo occurrences without confirmed maternity and paternity, and PM6 as at least 4 assumed de novo occurrences, in patients with FPD/AML phenotype.
  • The case evidence bundle provides no documented assumed de novo occurrence or qualifying FPD/AML phenotype for NM_001754.4:c.177C>T (p.Gly59=).
  • Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx, Results sheet: searches for c.177C>T, p.Gly59=, and p.G59= returned no matching row.
Still missing
  • No assumed de novo occurrences in patients with FPD/AML phenotype were identified in the case evidence bundle.
  • Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx was searched for c.177C>T, p.Gly59=, and p.G59=; no entry was found.
Sources
cspec ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results ↗
PP1 VCEPNot assessed: no countable genotype- and phenotype-positive family meioses or obligate carriers are documented for this variant. Details ▾Hide ▴
Reasoning

The VCEP assigns PP1_Supporting to 3 or 4 observed meioses, PP1_Moderate to 5 or 6, and PP1_Strong to at least 7, counting genotype- and phenotype-positive individuals and obligate carriers. The case evidence bundle contains no family segregation data or countable meioses for this variant. The governing RUNX1 pilot-results file was searched for c.177C>T, p.Gly59=, and p.G59=, with no matching entry.

Evidence considered
  • The RUNX1 CSPEC specifies PP1 for 3 or 4 meioses, PP1_Moderate for 5 or 6 meioses, and PP1_Strong for at least 7 meioses.
  • The case evidence bundle provides no family segregation data, genotype- and phenotype-positive relatives, obligate carriers, or meiosis count for NM_001754.4:c.177C>T (p.Gly59=).
  • Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx, Results sheet: searches for c.177C>T, p.Gly59=, and p.G59= returned no matching row.
Still missing
  • No family segregation observations or countable meioses were identified in the case evidence bundle.
  • Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx was searched for c.177C>T, p.Gly59=, and p.G59=; no entry was found.
Sources
cspec ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results ↗
BS3 VCEPNot assessed: no variant-specific transactivation result in the 80-115% wild-type range or normal secondary-assay result is available. Details ▾Hide ▴
Reasoning

The available case evidence contains no variant-specific transactivation result demonstrating normal activity in the VCEP range of 80-115% of wild type and no secondary assay demonstrating normal function. The VCEP's BS3 Strong conjunction therefore cannot be evaluated, and no benign functional evidence can be assigned.

VCEP rule
**BS3:** Transactivation assays demonstrating normal transactivation (80-115% of wt) AND data from a secondary assay demonstrating normal function.
Evidence considered
  • The VCEP BS3 Strong rule requires normal transactivation at 80-115% of wild type and normal function in a secondary assay.
  • The VCEP functional-study instructions specify wild-type and known-pathogenic controls and CBFβ co-expression for transactivation assays; no qualifying variant-specific assay results are present.
  • The available paper-extraction records contain no variant-specific functional study for NM_001754.4:c.177C>T (p.Gly59=).
Still missing
  • Variant-specific transactivation assay result quantified against wild type and appropriate controls.
  • Variant-specific secondary assay demonstrating normal RUNX1 function.
Sources
cspec ↗
BS4 VCEPNot assessed: no genotype-negative, phenotype-positive relatives or at least 2 informative meioses are documented for this variant. Details ▾Hide ▴
Reasoning

The VCEP limits BS4 to genotype-negative, phenotype-positive family members and specifies application when the finding is observed in at least 2 informative meioses. The case evidence bundle contains no such family observations or informative-meiosis count for this variant. The governing RUNX1 pilot-results file was searched for c.177C>T, p.Gly59=, and p.G59=, with no matching entry.

Evidence considered
  • The RUNX1 CSPEC states that BS4 is for genotype-negative, phenotype-positive family members and is applicable when observed in at least 2 informative meioses.
  • The case evidence bundle provides no genotype-negative, phenotype-positive family observations or informative-meiosis count for NM_001754.4:c.177C>T (p.Gly59=).
  • Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx, Results sheet: searches for c.177C>T, p.Gly59=, and p.G59= returned no matching row.
Still missing
  • No genotype-negative, phenotype-positive family members or informative meioses were identified in the case evidence bundle.
  • Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx was searched for c.177C>T, p.Gly59=, and p.G59=; no entry was found.
Sources
cspec ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results ↗
BP2 VCEPNot assessed: no documented cis/trans phase or pathogenic variant in cis or trans is available to evaluate the VCEP BP2 rule. Details ▾Hide ▴
Reasoning

The VCEP BP2 rule requires the variant to be observed in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant in any inheritance pattern. The available case evidence contains no documented cis/trans phase, affected-proband observation, or pathogenic variant in cis or trans, so BP2 cannot be evaluated.

VCEP rule
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
Evidence considered
  • The VCEP BP2 rule requires either observation in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observation in cis with a pathogenic variant in any inheritance pattern.
  • The case evidence reviewed provides no documented cis/trans phase, affected-proband observation, or pathogenic variant in cis or trans for NM_001754.4:c.177C>T.
Still missing
  • Documented cis/trans phase with a pathogenic variant and the relevant affected-proband or inheritance context are unavailable.
Sources
cspec ↗
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.177C>T is synonymous at Gly59, with no protein-length change and SpliceAI maximum delta 0.026. Details ▾Hide ▴
Reasoning

NM_001754.4:c.177C>T is a synonymous exon 4 variant, NP_001745.2:p.(Gly59=), so it does not create a premature termination codon, frameshift, or protein-length change. It is not a canonical splice-site variant, and the available SpliceAI maximum delta score is 0.026, indicating no significant predicted splice impact. Therefore, the VCEP PVS1 decision-tree pathway for loss-of-function or qualifying splice variants does not apply. The governing RUNX1 pilot-results file was searched for c.177C>T, p.Gly59=, and p.G59=; no exact entry was found.

VCEP rule
Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects.
Evidence considered
  • Case variant assessment: NM_001754.4:c.177C>T; NP_001745.2:p.(Gly59=); synonymous consequence; exon 4; not a canonical splice-consensus variant.
  • SpliceAI result: maximum delta score 0.026 (DS_AL 0.026, DS_DL 0.009, DS_AG 0.000, DS_DG 0.000), supporting no significant predicted splice impact.
  • Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx, Results sheet: the table was searched for c.177C>T, p.Gly59=, and p.G59=; no exact matching row was present.
Still missing
  • The file Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx was searched for c.177C>T, p.Gly59=, and p.G59=; no exact entry was found.
Sources
cspec ↗pvs1_variant_assessmentspliceai ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results ↗
PS1 N/ANot applicable: p.(Gly59=) is synonymous and therefore has no altered amino-acid change to match a pathogenic missense variant. Details ▾Hide ▴
Reasoning

The variant is synonymous, NP_001745.2:p.(Gly59=), so it does not produce an amino-acid change that can be the same as a previously established pathogenic amino-acid change. The governing PS1 rule is restricted to the same amino-acid change. The complete RUNX1 pilot-results file was searched for c.177C>T, p.Gly59=, and p.G59=; no entry was found.

VCEP rule
**PS1:** Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
  • Case normalization: NM_001754.4:c.177C>T produces NP_001745.2:p.(Gly59=), a synonymous variant.
  • ClinGen RUNX1 CSPEC v3.1, PS1 rule: same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
  • Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx, Results sheet: searches for c.177C>T, p.Gly59=, and p.G59= found no matching row.
Still missing
  • No c.177C>T, p.Gly59=, or p.G59= entry was found in Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx after searching each notation.
Sources
cspec ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results ↗
PM1 N/ANot applicable: residue 59 lies outside the VCEP-approved PM1 region, residues 89-204 within the RUNX1 RHD. Details ▾Hide ▴
Reasoning

The variant affects residue 59, whereas the RUNX1 VCEP PM1 rule applies to variants affecting residues 89-204 within the RHD, with PM1_strong limited to its listed critical residues. Residue 59 is outside the complete VCEP-defined PM1 region. vcep_materials.json has no domain_tables entry for RUNX1, so there is no additional authoritative domain list to inspect. The complete RUNX1 pilot-results file was searched for c.177C>T, p.Gly59=, and p.G59=; no entry was found.

VCEP rule
**PM1\_strong:** Variant affecting one of the following 13 AA residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204. ... **PM1\_Supporting**: Variant affecting one of the other AA residues 89-204 within the RHD.
Evidence considered
  • Case normalization identifies the affected amino-acid residue as Gly59.
  • ClinGen RUNX1 CSPEC v3.1, PM1 rule: PM1_supporting applies to other amino-acid residues 89-204 within the RHD; PM1_strong applies only to the separately listed critical residues.
  • vcep_materials.json: domain_tables is empty for RUNX1, so no additional authoritative domain-table entry applies.
  • Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx, Results sheet: searches for c.177C>T, p.Gly59=, and p.G59= found no matching row.
Still missing
  • No c.177C>T, p.Gly59=, or p.G59= entry was found in Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx after searching each notation.
Sources
cspec ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results ↗
PM3 VCEPNot applicable: the RUNX1 VCEP specification explicitly designates PM3 as not applicable. Details ▾Hide ▴
Reasoning

The RUNX1 VCEP specification explicitly marks PM3 as not applicable. Therefore, no assessment of phase, affected probands, or biallelic inheritance is performed for this criterion.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen Myeloid Malignancy VCEP RUNX1 Version 3.1 criteria entry for PM3: applicability is "Not Applicable."
Sources
cspec ↗
PM4 N/ANot applicable: the synonymous p.(Gly59=) variant has neither an in-frame indel nor a stop-loss protein extension. Details ▾Hide ▴
Reasoning

The VCEP PM4 rule applies to in-frame deletion/insertion variants or stop-loss variants causing a protein extension. NM_001754.4:c.177C>T is synonymous, p.(Gly59=), with no amino-acid deletion, insertion, or protein extension; PM4 therefore does not apply. The governing RUNX1 pilot-results file was searched for c.177C>T, p.Gly59=, and p.G59=; no exact entry was found.

VCEP rule
**For in-frame/indel variants:** **PM4_strong:** In-frame deletion/insertion impacting at least one of the following AA residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204. **For stop loss variants:** **PM4:** Stop-loss variant causing a protein extension.
Evidence considered
  • Case variant assessment: NM_001754.4:c.177C>T is synonymous and encodes NP_001745.2:p.(Gly59=), with no protein-length change.
  • ClinGen Myeloid Malignancy VCEP RUNX1 v3.1 PM4 rule: PM4 is defined for in-frame deletion/insertion variants and stop-loss variants causing a protein extension.
  • Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx, Results sheet: the table was searched for c.177C>T, p.Gly59=, and p.G59=; no exact matching row was present.
Still missing
  • The file Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx was searched for c.177C>T, p.Gly59=, and p.G59=; no exact entry was found.
Sources
cspec ↗pvs1_variant_assessmentvcep_myeloid_malignancy_vcep_runx1_pilot_results ↗
PM5 N/ANot applicable: PM5 requires a missense change, whereas c.177C>T is synonymous and produces p.(Gly59=). Details ▾Hide ▴
Reasoning

The variant is synonymous, p.(Gly59=), not a missense change. The VCEP PM5 rule is explicitly limited to a missense change at an amino-acid residue with a different pathogenic or likely pathogenic missense change. The complete RUNX1 pilot-results file was searched for c.177C>T, p.Gly59=, and p.G59=; no entry was found.

VCEP rule
**PM5:** Missense change at an AA residue where a different missense change which has been determined to be pathogenic before (after accounting for Grantham scores).
Evidence considered
  • Case normalization: NM_001754.4:c.177C>T produces NP_001745.2:p.(Gly59=), a synonymous variant.
  • ClinGen RUNX1 CSPEC v3.1, PM5 rule: a missense change at an amino-acid residue where a different missense change has previously been determined pathogenic or likely pathogenic.
  • Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx, Results sheet: searches for c.177C>T, p.Gly59=, and p.G59= found no matching row.
Still missing
  • No c.177C>T, p.Gly59=, or p.G59= entry was found in Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx after searching each notation.
Sources
cspec ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results ↗
PP2 VCEPNot applicable: the RUNX1 VCEP explicitly excludes PP2 because RUNX1 does not meet its missense-constraint requirement. Details ▾Hide ▴
Reasoning

The RUNX1 VCEP explicitly marks PP2 as Not applicable. Its criterion-specific instruction states that RUNX1 did not meet the recommended missense-constraint cutoff and has benign/likely benign missense variation; this criterion is not applied to the case.

VCEP rule
MM-VCEP notes: The recommended cutoff for PP2 by the SVI is a missense constraint z score of ≥ 3.09 which was not met by RUNX1 (2.48 on ExAC and 2.08 on gnomAD). In addition, there are 9 benign/likely benign missense RUNX1 variants in ClinVar.
Evidence considered
  • ClinGen RUNX1 CSPEC v3.1, PP2 entry: applicability is Not applicable; the VCEP notes a missense constraint z score of 2.48 on ExAC and 2.08 on gnomAD and 9 benign/likely benign RUNX1 missense variants in ClinVar.
Sources
cspec ↗
PP4 VCEPNot applicable: the RUNX1 VCEP rejects PP4 because FPD/AML is too nonspecific and has multiple possible genetic and environmental causes. Details ▾Hide ▴
Reasoning

PP4 is explicitly marked Not applicable in the RUNX1 VCEP. The VCEP states that the FPD/AML phenotype is rather unspecific and can be caused by other inherited predisposition syndromes, somatic mutations, or environmental factors, so it does not meet the original PP4 specificity requirement.

VCEP rule
The FPD/AML phenotype is rather unspecific and can be caused by a number of other inherited predisposition syndromes, somatic mutations or environmental factors that are insufficient to meet the original ACMG/AMP rule PP4.
Evidence considered
  • The RUNX1 VCEP CSPEC entry marks PP4 as Not applicable and gives the reason that FPD/AML is rather unspecific and can result from other inherited syndromes, somatic mutations, or environmental factors.
Sources
cspec ↗
PP5 VCEPNot applicable: the RUNX1 VCEP explicitly prohibits PP5 under the ClinGen SVI VCEP Review Committee recommendation. Details ▾Hide ▴
Reasoning

PP5 is explicitly not for use in this VCEP. The governing rule states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • The RUNX1 VCEP CSPEC entry marks PP5 Not Applicable for this VCEP and states that the criterion is not for use.
Sources
cspec ↗
BS2 VCEPNot applicable: the RUNX1 VCEP explicitly marks BS2 Not Applicable, regardless of the observed zero gnomAD homozygotes. Details ▾Hide ▴
Reasoning

BS2 is explicitly marked Not Applicable in the RUNX1 VCEP Version 3.1 criteria specification, so no homozygote or healthy-adult observation can activate this criterion under the governing framework. The governing RUNX1 pilot-results file was searched for c.177C>T, p.Gly59=, and p.G59=; no matching row was found.

VCEP rule
Not Applicable
Evidence considered
  • The RUNX1 VCEP Version 3.1 CSPEC criteria entry lists BS2 applicability as Not Applicable.
  • gnomAD v4.1 reports 0 homozygotes, but this observation is not used because the governing VCEP marks BS2 Not Applicable.
Still missing
  • No matching c.177C>T, p.Gly59=, or p.G59= entry was found in Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx.
Sources
cspec ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results ↗
BP1 VCEPNot applicable: the RUNX1 VCEP states that both truncating and missense variants cause FPD/AML, so BP1 does not apply. Details ▾Hide ▴
Reasoning

The RUNX1 VCEP explicitly marks BP1 as Not applicable because both truncating and missense variants cause FPD/AML. Therefore BP1 is not applied to this synonymous variant.

VCEP rule
MM-VCEP notes: BP1 is not applicable for RUNX1, because both truncating and missense variants cause FPD/AML.
Evidence considered
  • ClinGen RUNX1 CSPEC v3.1, BP1 entry: applicability is Not applicable because both truncating and missense variants cause FPD/AML.
Sources
cspec ↗
BP3 VCEPNot applicable: the RUNX1 VCEP specification explicitly designates BP3 as not applicable for this synonymous variant. Details ▾Hide ▴
Reasoning

The RUNX1 VCEP specification explicitly marks BP3 as not applicable. The variant is synonymous rather than an in-frame deletion or insertion in a repetitive region, and no BP3 pathway is available under this VCEP specification. The governing RUNX1 pilot-results file was searched for c.177C>T, p.Gly59=, and p.G59=; no exact entry was found.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen Myeloid Malignancy VCEP RUNX1 version 3.1 CSPEC entry for BP3: applicability is explicitly listed as Not Applicable.
  • Case variant assessment: NM_001754.4:c.177C>T is synonymous, NP_001745.2:p.(Gly59=), not an in-frame deletion or insertion.
  • Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx, Results sheet: the table was searched for c.177C>T, p.Gly59=, and p.G59=; no exact matching row was present.
Still missing
  • The file Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx was searched for c.177C>T, p.Gly59=, and p.G59=; no exact entry was found.
Sources
cspec ↗pvs1_variant_assessmentvcep_myeloid_malignancy_vcep_runx1_pilot_results ↗
BP5 VCEPNot applicable: the RUNX1 VCEP explicitly states that BP5 is not applicable despite rare patients carrying two hematologic-malignancy predisposition variants. Details ▾Hide ▴
Reasoning

BP5 is explicitly marked Not applicable in the RUNX1 VCEP. The VCEP notes that, although a patient can rarely carry two pathogenic variants in genes predisposing to hematologic malignancies, BP5 is not applicable.

VCEP rule
BP5 is not applicable. In rare circumstances, a patient can carry two pathogenic variants in genes predisposing to hematologic malignancies.
Evidence considered
  • The RUNX1 VCEP CSPEC entry marks BP5 Not applicable and states: BP5 is not applicable; in rare circumstances, a patient can carry two pathogenic variants in genes predisposing to hematologic malignancies.
Sources
cspec ↗

Identifiers

Gene
RUNX1
Transcript
NM_001754.4
Coding (HGVS c.)
NM_001754.4:c.177C>T
Protein (HGVS p.)
NP_001745.2:p.(Gly59=)
GRCh38
chr21:34887017 G>A
GRCh37
chr21:36259314 G>A
Location and type
Exon 4 · synonymous
ClinVar
739793

Gene diagram

Every interpreted variant in RUNX1, mapped onto the exon structure of NM_001754.4. Select a row to find it on the plot.

RUNX1NM_001754.4
Fetching transcript structure from UCSC…
gnomAD v4.1 6 / 1,601,944 alleles AF 3.75e-06 · 0 homozygotes · FAF 1.83e-06
gnomAD v2.1 1 / 230,042 alleles AF 4.35e-06 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 3.7e-06 · 6 / 1,601,944 alleles · 0 hom · FAF 1.8e-06
European (non-Finnish)6 / 1,178,148 5.1e-06
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 4.3e-06 · 1 / 230,042 alleles · 0 hom
European (non-Finnish)1 / 104,182 9.6e-06
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 3.74545e-06; MAF= 0.00037%, 6/1601944 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.09274e-06; MAF= 0.00051%, 6/1178148 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.34703e-06; MAF= 0.00043%, 1/230042 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.59859e-06; MAF= 0.00096%, 1/104182 alleles, homozygotes = 0).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +79 bp
0.026
SpliceAI acceptor gainat -154 bp
0.000
SpliceAI donor lossat +274 bp
0.009
SpliceAI donor gainat +139 bp
0.000
Pangolin splice lossmagnitude shown
-0.001
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingVCEPMet: SpliceAI maximum delta 0.026 is below the VCEP synonymous-variant BP4 cutoff of 0.20. Details ▾Hide ▴
Reasoning

The variant is synonymous and lies within exon 4 rather than a canonical splice site. The VCEP synonymous BP4 path requires SpliceAI <= 0.20. The observed maximum delta score is 0.026, satisfying that cutoff. The VCEP pilot-results file was searched for c.177C>T, p.Gly59=, and p.G59=; no entry for this variant was found, although its synonymous precedent rows assign BP4 at low SpliceAI-compatible evidence.

VCEP rule
For synonymous and Intronic variants: **BP4:** SpliceAI ≤ 0.20
Evidence considered
  • VCEP variant mapping places NM_001754.4:c.177C>T in exon 4 (coding interval c.98-c.351), not at a canonical splice site.
  • SpliceAI Lookup result for NM_001754.4:c.177C>T: maximum delta score=0.026, with DS_AL=0.026 and DS_DL=0.009.
  • Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx, Results sheet: searched c.177C>T, p.Gly59=, and p.G59= with no matching row; synonymous precedent rows c.1308C>T (p.Ser436=), c.891C>T (p.His297=), and c.510G>T (p.Gly170=) include BP4.
Still missing
  • No entry for c.177C>T, p.Gly59=, or p.G59= was found in Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx.
Sources
cspec ↗spliceai ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results ↗
BP7 SupportingVCEPMet: synonymous exon-4 variant has SpliceAI maximum delta 0.026, satisfying the VCEP BP7 cutoff of 0.20 outside excluded splice-adjacent positions. Details ▾Hide ▴
Reasoning

The variant is synonymous, is in exon 4 at c.177 within the exon interval c.98-c.351, and is not a canonical splice-site variant; therefore it is not within the VCEP's excluded last-three-donor or first-after-acceptor positions. The VCEP BP7 rule requires SpliceAI delta scores <= 0.20, and the maximum observed score is 0.026. The VCEP pilot-results file was searched for c.177C>T, p.Gly59=, and p.G59=; no entry for this variant was found, while synonymous precedent rows assign BP7 with BP4.

VCEP rule
**BP7:** Applicable for * Synonymous variants – excluding those in the last 3 nucleotides preceding a canonical donor splice site or the first nucleotide following a canonical acceptor splice site – with SpliceAI Δ scores ≤ 0.20. * Intronic variants with SpliceAI Δ scores ≤ 0.20. **BP7\_Variable (RNA):** * Applicable for variants with RNA data, with weighting based on the quality of the available RNA data.
Evidence considered
  • VCEP variant mapping places NM_001754.4:c.177C>T in exon 4, coding interval c.98-c.351; c.177 is not a canonical splice-site position or one of the excluded splice-adjacent positions.
  • SpliceAI Lookup result for NM_001754.4:c.177C>T: DS_AG=0.000, DS_AL=0.026, DS_DG=0.000, DS_DL=0.009; maximum delta score=0.026.
  • Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx, Results sheet: searched c.177C>T, p.Gly59=, and p.G59= with no matching row; synonymous precedent rows c.1308C>T (p.Ser436=), c.891C>T (p.His297=), and c.510G>T (p.Gly170=) include BP7.
Still missing
  • No entry for c.177C>T, p.Gly59=, or p.G59= was found in Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx.
Sources
cspec ↗spliceai ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results ↗
PP3 VCEPNot met: SpliceAI maximum delta 0.026 is below the VCEP synonymous-variant PP3 threshold of 0.38. Details ▾Hide ▴
Reasoning

The variant is synonymous (NM_001754.4:c.177C>T; NP_001745.2:p.(Gly59=)) in exon 4, so the VCEP's synonymous/intronic PP3 path applies and requires SpliceAI >= 0.38. SpliceAI's maximum delta score is 0.026 (DS_AL 0.026; DS_DL 0.009; DS_AG and DS_DG 0.000), which is below the PP3 threshold. The VCEP pilot-results file was searched for c.177C>T, p.Gly59=, and p.G59=; no entry for this variant was found. Its synonymous precedent rows show that PP3 is not assigned on the low-SpliceAI synonymous path, while PP3 is assigned to selected missense variants; those precedents are not used as a classification substitute.

VCEP rule
For synonymous and intronic (intron 4-8) variants: **PP3:** SpliceAI ≥ 0.38, including the creation of cryptic novel splice sites. Caveats: *Do not use for variants with a predicted splicing effect that is proven by RNA analysis. See **PVS1\_Variable (RNA)**. *Do not use for for canonical splice site variants.
Evidence considered
  • VCEP CSPEC identifies the variant as synonymous: NM_001754.4:c.177C>T, NP_001745.2:p.(Gly59=), in exon 4.
  • SpliceAI Lookup result for NM_001754.4:c.177C>T: DS_AG=0.000, DS_AL=0.026, DS_DG=0.000, DS_DL=0.009; maximum delta score=0.026.
  • Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx, Results sheet: searched c.177C>T, p.Gly59=, and p.G59= with no matching row; synonymous precedent rows c.1308C>T (p.Ser436=), c.891C>T (p.His297=), and c.510G>T (p.Gly170=) apply BP4/BP7 rather than PP3.
Still missing
  • No entry for c.177C>T, p.Gly59=, or p.G59= was found in Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx.
Sources
cspec ↗spliceai ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • ACMG position statement on prenatal/preconception expanded carrier screening.
    This paper is an ACMG policy statement on prenatal/preconception expanded carrier screening. It does not mention RUNX1, c.177C>T, NP_001745.2:p.(G59=), or provide variant-specific clinical or prevalence evidence relevant to this group.
    Does not name this variant
    PMID 23619275 ↗
  • Appropriateness of newborn screening for &#x3b1;1-antitrypsin deficiency.
    Teckman J et al. · 2014
    This paper concerns SERPINA1-related alpha-1-antitrypsin deficiency and does not mention RUNX1, c.177C>T, or p.(G59=); it provides no evidence relevant to PS4 or PP5 for this variant.
    Does not name this variant
    PMID 24121147 ↗
    Quoted passage
    α-1-Antitrypsin (AAT) deficiency is a metabolic-genetic disease that, in its classical and most typical form, is caused by homozygosity for the AAT mutant Z gene (SERPINA1).

    Introduction, first paragraph

  • RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies.
    Adam MP et al. · 1993
    No paper-specific finding is recorded.
    PMID 33661592 ↗
  • Offering prenatal diagnostic tests: European guidelines for clinical practice [corrected].
    No paper-specific finding is recorded.
    PMID 24022298 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    No paper-specific finding is recorded.
    PMID 28492532 ↗
  • ACOG Committee Opinion No. 778 Summary: Newborn Screening and the Role of the Obstetrician-Gynecologist.
    No paper-specific finding is recorded.
    PMID 31022120 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 6 / 1,601,944 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.026 Open source ↗
ClinVar 2 Likely benign Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 3.74545e-06; MAF= 0.00037%, 6/1601944 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.09274e-06; MAF= 0.00051%, 6/1178148 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.34703e-06; MAF= 0.00043%, 1/230042 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.59859e-06; MAF= 0.00096%, 1/104182 alleles, homozygotes = 0).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely benign (2 clinical laboratories) and as Likely benign by ClinGen Myeloid Malignancy Variant Curation Expert Panel (expert panel). (ClinVarID = 739793)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.