Classification rationale

BP4BP6BP7 Likely Benign

RUNX1 c.444C>T

The RUNX1 c.444C>T (p.Thr148=) variant is reported in ClinVar and is currently classified as Likely Benign by the ClinGen Myeloid Malignancy Variant Curation Expert Panel.¹ This variant is present in population databases, including gnomAD v4.1 with grpmax FAF 7.574e-05 and gnomAD v2.1 with grpmax FAF 6.015e-05; these values are above the RUNX1 PM2_Supporting threshold of 0.00005 and below the RUNX1 BS1 threshold of 0.00015.² In silico splicing prediction does not support a splice-disrupting effect, with SpliceAI max delta score 0.01, which is below the RUNX1 PP3 threshold of 0.38 and within the BP4 and BP7 benign threshold of 0.20.³

BP4 + BP6 + BP7 → Likely Benign

1 clinvar ↗

2 gnomad_v4 ↗gnomad_v2 ↗cspec ↗

3 spliceai ↗cspec ↗

Gene diagram · NM_001754.4 · variants mapped to exon structure

RUNX1 NM_001754.4

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

PS

PM

PP

Benign evidence

BA

BS

BP

—

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= 7.68253e-05; MAF= 0.00768%, 124/1614052 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.98323e-05; MAF= 0.00898%, 106/1179976 alleles, homozygotes = 0); grpmax FAF= 7.574e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 5.65859e-05; MAF= 0.00566%, 16/282756 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.29411e-05; MAF= 0.00929%, 12/129114 alleles, homozygotes = 0); grpmax FAF= 6.015e-05.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0077% · 124 / 1,614,052
0 hom · FAF 0.0076%

European (non-Finnish) 106 / 1,179,976	0.009%
Remaining individuals 5 / 62,496	0.008%
African/African American 5 / 75,018	0.0067%
East Asian 2 / 44,886	0.0045%
South Asian 4 / 91,082	0.0044%
Ashkenazi Jewish 1 / 29,608	0.0034%
European (Finnish) 1 / 64,016	0.0016%

+ 3 not observed (Admixed American, Amish, Middle Eastern)

gnomAD v2.1

0.0057% · 16 / 282,756
0 hom · FAF 0.006%

European (non-Finnish) 12 / 129,114	0.0093%
African/African American 2 / 24,962	0.008%
South Asian 2 / 30,614	0.0065%

+ 5 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Likely Benign 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 = 0.01).

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; COSV55872606, n = 2 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