Classification rationale

PM2 BP4BP7 Likely Benign

RUNX1 c.1113C>T

The RUNX1 c.1113C>T (p.Ala371=; p.A371=) variant has been reported in ClinVar, where the aggregate record is Uncertain Significance with expert panel review and includes two likely benign laboratory submissions.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing the observed population frequency at 0 and below the RUNX1 PM2_supporting threshold of 0.00005.² SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, which is below the RUNX1 PP3 threshold of 0.38 and at or below the BP4 and BP7 threshold of 0.20 for synonymous variants.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 · 13 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 Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0, which is below the RUNX1 PM2_supporting threshold of 0.00005.

Absent from gnomAD v2.1.Absent from gnomAD v4.1.RUNX1 PM2_supporting threshold <= 0.00005.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting Benign

For synonymous RUNX1 variants, BP4 applies when SpliceAI is 0.20 or lower. This variant has a SpliceAI maximum delta score of 0.00, supporting no predicted splice impact.

SpliceAI max delta score 0.00.RUNX1 BP4 threshold <= 0.20 for synonymous variants.

cspec ↗spliceai ↗

BP7 supporting Benign

This synonymous variant is not at a canonical splice-site boundary position used to exclude BP7, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is at or below the RUNX1 BP7 threshold of 0.20.

Protein consequence p.(Ala371=).SpliceAI max delta score 0.00.RUNX1 BP7 threshold <= 0.20 for eligible synonymous variants.

cspec ↗spliceai ↗

Assessed · not applied · 5 not met · 8 not assessed

Pathogenic

PVS1 This synonymous variant is not a nonsense, frameshift, or canonical splice-site variant, and SpliceAI predicts no significant splice impact (max delta score 0.00).

PS2 No proven de novo occurrence with confirmed maternity and paternity was identified for this variant in a patient with a RUNX1-related phenotype.

PS3 No published functional study or RNA assay was identified showing an abnormal effect for this exact variant.

PS4 This variant is present in ClinVar, but no exact proband count meeting RUNX1 phenotypic criteria was identified to support case enrichment.

PM1 This variant is a synonymous change at Ala371, which is outside the RUNX1 Runt homology domain hotspot region defined for PM1 (residues 89-204).

PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant in a patient with a RUNX1-related phenotype.

PP1 No segregation data were identified showing that this variant tracks with a RUNX1-related phenotype in informative meioses.

PP3 For synonymous RUNX1 variants, PP3 requires SpliceAI at least 0.38.

Benign

BA1 This variant is absent from gnomAD, so the observed population frequency is 0 and does not reach the RUNX1 BA1 threshold of at least 0.0015.

BS1 This variant is absent from gnomAD, so the observed population frequency is 0 and does not fall within the RUNX1 BS1 range of 0.00015 to 0.0015.

BS3 No published RNA study or other functional assay was identified showing normal function for this exact variant.

BS4 No family data were identified showing that this variant fails to segregate with a RUNX1-related phenotype across informative meioses.

BP2 No data were identified showing this variant in trans with a pathogenic RUNX1 variant or in cis with a pathogenic variant.

N/A · 12 PS1 · PM3 · PM4 · PM5 · PP2 · PP4 · PP5 · BS2 · BP1 · BP3 · BP5 · BP6

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

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 (2 clinical laboratories) 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).

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 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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