Starting

Initialising…

RUNX1

Final classification

VUS

RUNX1 c.1094A>C · p.Gln365Pro

RUNX1

Gene

RUNX1

Transcript

NM_001001890.2

HGVS · transcript:coding

NM_001001890.2:c.1094A>C

Consequence

N/A

GRCh38

chr21:34792403 T>G

GRCh37

chr21:36164700 T>G

Basis Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework: PM2 supporting (+1) + BP4 supporting (-1) = 0 points, which maps to VUS. ▾

Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework: PM2 supporting (+1) + BP4 supporting (-1) = 0 points, which maps to VUS.

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 ↗

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

RUNX1 NM_001001890.2

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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