NM_001754.4:c.1265A>C (p.Glu422Ala) is a missense variant in RUNX1 exon 9, assessed under the ClinGen Myeloid Malignancy VCEP RUNX1 specification v3.1.1 BA1 is met at stand-alone strength: the variant is present in gnomAD v4.1 with an East Asian allele frequency of 0.466% (137/29,388 alleles), Ashkenazi Jewish AF of 0.433% (102/23,548 alleles), and European non-Finnish AF of 0.163% (1,509/926,052 alleles), all exceeding the VCEP BA1 threshold of ≥ 0.15% in a general continental population with ≥ 2,000 alleles and ≥ 5 variant alleles.2 BP4 is met at supporting benign strength: REVEL score of 0.052 is below 0.50 and SpliceAI max delta of 0.00 is ≤ 0.20, meeting the VCEP threshold for multiple lines of computational evidence suggesting no impact.3 No pathogenic criteria are met. PVS1 is not applicable (missense variant). PM1 is not met (E422 is outside the RHD domain, residues 89-204). PM2 is not met (allele frequency far exceeds the 0.005% threshold). PP3 is not met (REVEL 0.052 << 0.88 threshold). No functional, segregation, de novo, proband, or same-residue pathogenic evidence was identified in the reviewed literature. Under the Tavtigian point-based classification system adopted by the MM-VCEP, BA1 (stand-alone benign) directs a final classification of Benign regardless of other criteria.4
RUNX1
Final classification
Benign
RUNX1 c.1265A>C · p.Glu422Ala
RUNX1
NM_001754.4:c.1265A>C (p.Glu422Ala) is a missense variant in RUNX1 exon 9, assessed under the ClinGen Myeloid Malignancy VCEP RUNX1 specification v3.1.
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.1265A>C
BA1 + BP4
→
Benign
Gene diagram
· NM_001754.4 · variants mapped to exon structure
RUNX1
NM_001754.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 15 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
BA1
stand-alone
Benign
The variant has a minor allele frequency ≥ 0.15% in multiple general continental populations with ≥ 2,000 alleles and ≥ 5 variant alleles. gnomAD v4.1 East Asian AF = 0.466% (137/29,388 alleles), Ashkenazi Jewish AF = 0.433% (102/23,548 alleles), European non-Finnish AF = 0.163% (1,509/926,052 alleles). GrpMax FAF = 0.403%. Each exceeds the VCEP BA1 threshold of 0.15%.
East Asian AF=0.466%137 alleles in 29388
✓
BP4
supporting
Benign
For missense variants, the VCEP BP4 rule requires REVEL < 0.50 AND SpliceAI ≤ 0.20. This variant has REVEL = 0.052 and SpliceAI max delta = 0.00, both meeting the BP4 thresholds. Multiple lines of computational evidence suggest no deleterious impact.
REVEL=0.052 (<0.50)SpliceAI max delta=0.00 (≤0.20)BayesDel=-0.3919 (benign-leaning).
Assessed · not applied
Pathogenic
PVS1
NM_001754.4:c.1265A>C is a missense variant (p.Glu422Ala) and does not fall into any PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus).
PS1
p.Glu422Ala (E422A) has not been previously established as a pathogenic or likely pathogenic variant by the MM-VCEP.
PS2
No de novo occurrence (proven or assumed) was identified for NM_001754.4:c.1265A>C in any reviewed publication or ClinVar submission.
PS3
No functional studies testing NM_001754.4:c.1265A>C (p.Glu422Ala) or a systematically characterized range including codon 422 were identified.
PS4
No probands meeting RUNX1-phenotypic criteria were identified for this variant in the reviewed literature or ClinVar submissions.
PM1
The variant p.Glu422Ala lies at codon 422, which is well outside the Runt homology domain (RHD, residues 89-204).
PM2
The VCEP PM2_Supporting threshold requires MAF ≤ 0.00005 (0.005%).
PM5
No different missense change at codon 422 has been established as pathogenic or likely pathogenic by the MM-VCEP.
PM6
No assumed de novo occurrences were identified for this variant in any reviewed publication or ClinVar record.
PP1
No co-segregation data (informative meioses) were identified for this variant in any reviewed publication or case material.
PP3
For missense variants, the VCEP PP3 rule requires REVEL ≥ 0.88 or SpliceAI ≥ 0.38.
Benign
BS1
BS1 is superseded by BA1, which already applies at a higher (stand-alone) strength.
BS3
No functional studies demonstrating normal transactivation (80-115% of wild-type) or normal function in secondary assays were identified for p.Glu422Ala.
BS4
No segregation data demonstrating lack of segregation in ≥ 2 informative meioses were identified for this variant.
BP2
No evidence of this variant observed in trans with a pathogenic RUNX1 variant or in cis with a pathogenic variant was identified.
N/A · 8
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= 0.00174553; MAF= 0.17455%, 2207/1264374 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00466177; MAF= 0.46618%, 137/29388 alleles, homozygotes = 0); grpmax FAF= 0.00402616.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0002440214738897023, 2/8196 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.17%
· 2207 / 1,264,374
0 hom · FAF 0.4%
0 hom · FAF 0.4%
East Asian 137 / 29,388 |
0.47% |
Ashkenazi Jewish 102 / 23,548 |
0.43% |
Remaining individuals 168 / 47,400 |
0.35% |
European (Finnish) 126 / 41,164 |
0.31% |
European (non-Finnish) 1509 / 926,052 |
0.16% |
Middle Eastern 8 / 4,978 |
0.16% |
African/African American 90 / 65,062 |
0.14% |
Admixed American 44 / 46,730 |
0.094% |
South Asian 23 / 79,184 |
0.029% |
+ 1 not observed (Amish)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
0.024%
· 2 / 8,196
0 hom · FAF 0.055%
0 hom · FAF 0.055%
indel · split
East Asian 2 / 640 |
0.31% |
+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, European (Finnish), Middle Eastern, European (non-Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Uncertain Significance by ClinGen Myeloid Malignancy Variant Curation Expert Panel (expert panel). (ClinVarID = 988848)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.052. BayesDel score = -0.391942.
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; COSV114455125, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 7 PMIDs not cited in assessment
22138009 ↗
NCCN Task Force report: Evaluating the clinical utility of tumor markers in oncology.
CLINVAR
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
23970018 ↗
Acute myeloblastic leukaemias in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR
32171751 ↗
Acute myeloid leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
CLINVAR