Classification rationale

PM2 BP4BP7 Likely Benign

RUNX1 c.393T>C

The RUNX1 NM_001001890.2:c.393T>C (p.(Phe131=)) variant has been reported in ClinVar, where the ClinGen Myeloid Malignancy Variant Curation Expert Panel classified the equivalent RUNX1 transcript representation as uncertain significance and one clinical laboratory classified it as likely benign.¹ This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 (1/1614108 alleles; AF 6.20e-07), with the highest observed subpopulation frequency of 1.67e-05 remaining below the RUNX1 PM2_Supporting threshold of 0.00005.² Computational splicing prediction shows no significant splice impact, with a SpliceAI maximum delta score of 0.07, which supports BP4 and BP7 and does not meet the RUNX1 PP3 threshold.³

PM2 + BP4 + BP7 → Likely Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗cspec ↗

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.

Gene diagram · NM_001001890.2 · variants mapped to exon structure

RUNX1 NM_001001890.2

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 16 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

PM2 supporting review Pathogenic

This variant is absent from gnomAD v2.1 and is present at extremely low frequency in gnomAD v4.1 (1/1614108 alleles; AF 6.20e-07). The highest observed subpopulation frequency is 1/60016 in Admixed American individuals (AF 1.67e-05), which is below the RUNX1 PM2_Supporting threshold of 0.00005.

gnomAD v2.1 absentgnomAD v4.1 total AF 6.195372304703279e-07Highest observed subpopulation AF 1.666222340709144e-05 in AMR

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting review Benign

For synonymous RUNX1 variants, BP4 is met when SpliceAI is <=0.20. This variant has a SpliceAI maximum delta score of 0.07, supporting no significant predicted splice impact.

SpliceAI max delta score 0.07RUNX1 pilot results include synonymous variants curated with BP4/BP7 as benign-supporting evidence patterns.

cspec ↗spliceai ↗

BP7 supporting review Benign

This variant is synonymous, lies within exon 2 and not within the last 3 nucleotides before a donor site or the first nucleotide after an acceptor site, and SpliceAI predicts no significant splice impact (maximum delta score 0.07). These findings meet the RUNX1 BP7 rule.

Exon 2 spans c.271-c.427c.393 is internal to the exon.SpliceAI max delta score 0.07

cspec ↗spliceai ↗

Assessed · not applied · 8 not met · 8 not assessed

Pathogenic

PVS1 This synonymous variant does not fall within the RUNX1 loss-of-function variant categories used for PVS1, and available splicing prediction does not support a splice-disrupting effect.

PS1 No evidence was identified that this variant produces the same established pathogenic or likely pathogenic amino acid or splice effect as another RUNX1 variant.

PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant.

PS3 No published functional study was identified showing an abnormal effect of this specific variant on RUNX1 transactivation, secondary functional assays, or splicing.

PS4 This variant has been reported in ClinVar, but the available evidence does not document the number of unrelated affected probands meeting RUNX1 phenotypic criteria that would be required for PS4.

PM1 This synonymous variant does not meet the RUNX1 PM1 rule, which is specified for protein-altering variants affecting defined critical residues or other amino acids within the Runt homology domain.

PM4 This variant is a synonymous substitution and does not cause an in-frame insertion/deletion or stop-loss protein extension, so PM4 is not met.

PM5 This variant is synonymous and does not represent a missense change at a residue with previously established pathogenic missense variation.

PM6 No assumed de novo occurrence was identified for this variant.

PP1 No segregation data were identified for this variant in affected relatives.

PP3 For synonymous RUNX1 variants, PP3 requires SpliceAI >=0.38.

Benign

BA1 The observed population frequency is far below the RUNX1 BA1 threshold.

BS1 The observed population frequency does not reach the RUNX1 BS1 range.

BS3 No functional study was identified showing normal splicing or other normal function for this specific variant.

BS4 No nonsegregation data were identified for this variant.

BP2 No evidence was identified that this variant occurs in trans with a pathogenic RUNX1 variant, in cis with a pathogenic variant, or in a homozygous state in an unaffected context.

N/A · 9 PM3 · PP2 · PP4 · PP5 · BS2 · BP1 · BP3 · BP5 · BP6

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.19537e-07; MAF= 0.00006%, 1/1614108 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66622e-05; MAF= 0.00167%, 1/60016 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

6.2e-05% · 1 / 1,614,108
0 hom

Admixed American

1 / 60,016

0.0017%

+ 9 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (1 clinical laboratory) and as Uncertain Significance by ClinGen Myeloid Malignancy Variant Curation Expert Panel (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).

SpliceAI ↗

Functional Unknown Oncogenic Effect

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

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55866238, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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