NM_001754.4:c.1270T>G (p.Ser424Ala) is present in gnomAD v4.1 at an allele frequency of 1.05% in the East Asian population (255/24222 alleles, 0 homozygotes), exceeding the BA1 stand-alone benign threshold of 0.15% for RUNX1.1 Multiple in silico predictors support a benign effect: REVEL score 0.284, BayesDel score -0.238, and SpliceAI max delta score 0.00 indicate no predicted impact on protein function or splicing, meeting BP4 at supporting benign strength per RUNX1 VCEP specifications.2 The variant is absent from gnomAD v2.1 but is well-represented in gnomAD v4.1 (3159 total alleles), indicating that the larger, more diverse v4.1 dataset captures population variation not visible in earlier releases.3 No pathogenic evidence identified: no functional studies, no segregation data, no de novo occurrences, and no probands meeting RUNX1 phenotypic criteria were found in the available literature or databases.4 A single somatic occurrence has been reported in COSMIC (COSV99038603, n=1), which is not sufficient to support pathogenicity in the germline context. ClinVar classification is Uncertain Significance by the ClinGen Myeloid Malignancy VCEP (expert panel reviewed). This assessment incorporates updated gnomAD v4.1 population data not available at the time of that classification.5
RUNX1
Final classification
Benign
RUNX1 c.1270T>G · p.Ser424Ala
RUNX1
NM_001754.4:c.1270T>G (p.Ser424Ala) is present in gnomAD v4.1 at an allele frequency of 1.05% in the East Asian population (255/24222 alleles, 0 homozygotes), exceeding the BA1 stand-alone benign threshold of 0.15% for RUNX1.
ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RUNX1 Version 3.1 v3.1 point-based framework: BA1 stand-alone benign (-8) + BP4 supporting benign (-1) = -9 points, which maps to Benign.
Classification rationale
BA1BP4
Benign
RUNX1 c.1270T>G
BA1 + BP4
→
Benign
2
revelspliceai ↗bayesdelcspec ↗
Gene diagram
· NM_001754.4 · variants mapped to exon structure
RUNX1
NM_001754.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 14 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
BA1
stand-alone
Benign
The variant has a minor allele frequency of 1.05% in the East Asian population (gnomAD v4.1: 255/24222 alleles), exceeding the VCEP BA1 threshold of ≥0.15% in a continental population with ≥2000 alleles and ≥5 variant alleles. This high population frequency is incompatible with a highly penetrant autosomal dominant disorder.
EAS MAF=1.05276% (255/24222 alleles)exceeding BA1 threshold of ≥0.15%grpmax FAF=0.95%.
✓
BP4
supporting
Benign
REVEL score 0.284 (<0.50) and SpliceAI max delta score 0.00 (≤0.20) meet the VCEP BP4 criteria for missense variants. Multiple in silico predictors (REVEL, BayesDel) indicate a benign computational profile with no predicted splicing impact.
REVEL=0.284 (<0.50)SpliceAI max delta=0.00 (≤0.20)BayesDel=-0.238 (benign-leaning).
Assessed · not applied
Pathogenic
PS1
No prior classification of the same amino acid change (p.Ser424Ala) as pathogenic or likely pathogenic exists.
PS2
No de novo occurrence data available in the literature or ClinVar.
PS3
No variant-specific functional data identified.
PS4
No probands meeting RUNX1-phenotypic criteria (FPD/AML) identified in the available evidence.
PM1
p.Ser424 is located in the C-terminal region of RUNX1, outside the Runt homology domain (RHD, residues 89–204) defined by the VCEP for PM1 application.
PM2
gnomAD v4.1 overall allele frequency is 0.274% (3159/1152872 alleles), far exceeding the VCEP PM2_Supporting threshold of ≤0.005% (MAF ≤0.00005).
PM5
No other missense variants at codon 424 classified as pathogenic or likely pathogenic identified in ClinVar.
PM6
No assumed or confirmed de novo occurrences identified.
PP1
No co-segregation data available.
PP3
REVEL score 0.284 is below the 0.88 threshold and SpliceAI max delta 0.00 is below the 0.38 threshold required for PP3 under VCEP specifications.
Benign
BS1
The variant allele frequency (EAS 1.05%, overall 0.27%) exceeds the BS1 range of 0.015%–0.15%.
BS3
No functional studies demonstrating normal RUNX1 transactivation (80–115% of wild-type) identified.
BS4
No segregation data available to assess lack of segregation in affected families.
BP2
No evidence of this variant occurring in trans with a known pathogenic RUNX1 variant or in a homozygous state in unaffected individuals.
N/A · 9
PVS1 · PP2 · PP4 · PP5 · BS2 · BP1 · BP5 · BP6 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.00274011; MAF= 0.27401%, 3159/1152872 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.0105276; MAF= 1.05276%, 255/24222 alleles, homozygotes = 0); grpmax FAF= 0.00946718.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0003959611958028113, 4/10102 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.27%
· 3159 / 1,152,872
0 hom · FAF 0.95%
0 hom · FAF 0.95%
East Asian 255 / 24,222 |
1.1% |
Ashkenazi Jewish 171 / 21,980 |
0.78% |
European (Finnish) 234 / 38,078 |
0.61% |
Remaining individuals 247 / 42,882 |
0.58% |
Middle Eastern 18 / 4,708 |
0.38% |
European (non-Finnish) 1956 / 833,514 |
0.23% |
Admixed American 103 / 45,624 |
0.23% |
African/African American 125 / 63,640 |
0.2% |
South Asian 50 / 77,354 |
0.065% |
+ 1 not observed (Amish)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
0.04%
· 4 / 10,102
0 hom · FAF 0.046%
0 hom · FAF 0.046%
indel · split
East Asian 2 / 768 |
0.26% |
Remaining individuals 1 / 594 |
0.17% |
South Asian 1 / 808 |
0.12% |
+ 6 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, European (Finnish), Middle Eastern, European (non-Finnish))
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). (ClinVarID = 988867)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.284. BayesDel score = -0.237899.
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
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; COSV99038603, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 1 PMID not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR