Classification rationale

PM2 BP4 VUS

RUNX1 c.1094A>C

The RUNX1 NM_001001890.2:c.1094A>C (p.Gln365Pro, p.Q365P) variant has been reported in ClinVar and is currently classified there as a variant of uncertain significance by the ClinGen Myeloid Malignancy Variant Curation Expert Panel.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, with 0/1565090 alleles observed in gnomAD v4.1, which supports very low population frequency for RUNX1 disease.² Computational evidence does not support a damaging effect, with REVEL 0.245, SpliceAI maximum delta score 0.00, and BayesDel -0.122289; these findings support BP4 and do not support PP3.³

PM2 + BP4 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 revelspliceai ↗bayesdelcspec ↗

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 · 2 applied · 15 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 · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and is also absent from gnomAD v4.1, with 0/1565090 alleles observed overall and 0/73964 alleles in the highest observed subpopulation. The observed frequency is below the RUNX1 VCEP PM2_Supporting threshold of 0.00005, so PM2_Supporting is met.

gnomAD v2.1: absent.gnomAD v4.1: 0/1565090 allelesAF 0.0.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting Benign

For this missense variant, REVEL is 0.245, which is below the RUNX1 VCEP BP4 threshold of 0.50, and SpliceAI shows a maximum delta score of 0.00, which is at or below the BP4 threshold of 0.20. BayesDel is also negative at -0.122289, which does not support a damaging effect. These computational results support BP4.

REVEL score 0.245.SpliceAI max delta score 0.00.BayesDel score -0.122289.

cspec ↗spliceai ↗

Assessed · not applied · 5 not met · 10 not assessed

Pathogenic

PVS1 This is a missense variant, not a nonsense, frameshift, or canonical splice-site variant, and SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.00.

PS1 No previously established pathogenic or likely pathogenic variant with the same amino acid change was identified in the reviewed ClinVar summary or RUNX1 VCEP pilot materials, so PS1 cannot be applied from the available evidence.

PS2 No confirmed de novo occurrence with documented maternity and paternity confirmation was identified, so PS2 cannot be applied.

PS3 No well-established functional study showing abnormal RUNX1 function for this specific variant was identified, so PS3 cannot be assessed.

PS4 This variant is reported in ClinVar, but no proband-level evidence was identified showing 1 or more affected individuals meeting RUNX1 VCEP phenotypic criteria.

PM1 The RUNX1 VCEP PM1 region is restricted to residues 89-204 within the Runt homology domain, with stronger weighting for 13 specific residues.

PM5 No previously established pathogenic or likely pathogenic missense variant at this amino acid residue was identified in the reviewed evidence, so PM5 cannot be applied from the available materials.

PM6 No assumed de novo occurrences without parentage confirmation were identified, so PM6 cannot be assessed.

PP1 No segregation data were identified to show that this variant tracks with RUNX1-related disease in affected relatives, so PP1 cannot be assessed from the available evidence.

PP3 For this missense variant, REVEL is 0.245, which is below the RUNX1 VCEP PP3 threshold of 0.88, and SpliceAI shows a maximum delta score of 0.00, which is below the PP3 threshold of 0.38.

Benign

BA1 This variant is absent from gnomAD, with 0/1565090 alleles observed in gnomAD v4.1.

BS1 This variant is absent from gnomAD, with 0/1565090 alleles observed in gnomAD v4.1.

BS3 No well-established functional study showing normal RUNX1 function for this specific variant was identified, so BS3 cannot be assessed.

BS4 No non-segregation data with at least 2 informative meioses were identified, so BS4 cannot be assessed.

BP2 No data were identified showing this variant in trans with a pathogenic variant or in cis with a pathogenic variant, so BP2 cannot be assessed.

N/A · 11 PM3 · PM4 · PP2 · PP4 · PP5 · BS2 · BP1 · BP3 · BP5 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1565090 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/73964 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / 1,565,090
0 hom

Not observed in any ancestry group.

+ 10 not observed (Remaining individuals, Admixed American, 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 Uncertain significance (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 = 0.00). REVEL score = 0.245. BayesDel score = -0.122289.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RUNX1, a transcription factor involved in hematopoietic differentiation, is altered by mutation or chromosomal rearrangement in various hematologic ma

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

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

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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