Starting

Initialising…

RUNX1

Final classification

Likely Benign

RUNX1 c.393T>C · p.Phe131=

RUNX1

Gene

RUNX1

Transcript

NM_001001890.2

HGVS · transcript:coding

NM_001001890.2:c.393T>C

Consequence

N/A

GRCh38

chr21:34880591 A>G

GRCh37

chr21:36252888 A>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) + BP7 supporting (-1) = -1 points, which maps to Likely Benign. ▾

Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework: PM2 supporting (+1) + BP4 supporting (-1) + BP7 supporting (-1) = -1 points, which maps to Likely Benign.

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 ↗

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

RUNX1 NM_001001890.2

Fetching transcript structure from UCSC…

Applied criteria · 3 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 · 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