NM_001754.4:c.1252A>T (p.Met418Leu) in RUNX1 is classified as Benign per the ClinGen Myeloid Malignancy VCEP RUNX1 specifications v3.1.1 BA1 is met at stand-alone benign strength: the variant has an allele frequency of 0.507% in the East Asian population (gnomAD v4.1, 119/23,476 alleles, 0 homozygotes), exceeding the MM-VCEP BA1 threshold of ≥0.15% with ≥2,000 alleles tested and ≥5 variant alleles.2 BP4 is met at supporting benign strength: REVEL score 0.219 (<0.50) and SpliceAI max delta 0.00 (≤0.20) indicate a benign in silico prediction per MM-VCEP thresholds.3 BP6 is met at supporting benign strength: the ClinGen Myeloid Malignancy VCEP expert panel (3-star review) classified this variant as Benign (ClinVar ID 1703790).4 The variant is a missense change (p.Met418Leu) in the C-terminal region of RUNX1, outside the Runt homology domain (residues 89–204). No pathogenic criteria are met.5 Point-based classification (Tavtigian 2020): BA1 (-8) + BP4 (-1) + BP6 (-1) = −10 points, meeting the Benign threshold (≤−7).6
RUNX1
Final classification
Benign
RUNX1 c.1252A>T · p.Met418Leu
RUNX1
NM_001754.4:c.1252A>T (p.Met418Leu) in RUNX1 is classified as Benign per the ClinGen Myeloid Malignancy VCEP RUNX1 specifications 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) + BP6 supporting benign (-1) = -10 points, which maps to Benign.
Classification rationale
BA1BP4BP6
Benign
RUNX1 c.1252A>T
BA1 + BP4 + BP6
→
Benign
Gene diagram
· NM_001754.4 · variants mapped to exon structure
RUNX1
NM_001754.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 14 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
BA1
stand-alone
Benign
The variant has a minor allele frequency of 0.50690% (119/23,476 alleles) in the East Asian population in gnomAD v4.1, exceeding the MM-VCEP BA1 threshold of ≥0.15% in a general continental population dataset with ≥2,000 alleles and ≥5 variant alleles. This alone is sufficient to classify the variant as benign.
EAS AF=0.50690% (119/23476 alleles0 homozygotes)
✓
BP4
supporting
Benign
REVEL score is 0.219 (<0.50) and SpliceAI max delta score is 0.00 (≤0.20), meeting the MM-VCEP BP4 threshold for missense variants. Multiple in silico predictors support a benign interpretation.
REVEL=0.219 (<0.50)SpliceAI max delta=0.00 (≤0.20)BayesDel=-0.19 (negative score consistent with benign)
✓
BP6
supporting
Benign
Expert panel ClinGen Myeloid Malignancy Variant Curation Expert Panel classified as Benign.
ClinVar EP (ClinGen MM-VCEP) classification: Benignreviewed by expert panel (3-star)ClinVar expert panel classification
Assessed · not applied
Pathogenic
PS1
No evidence that the same amino acid change (p.Met418Leu) has been previously established as pathogenic or likely pathogenic via a different nucleotide change.
PS2
No proven de novo occurrences (with maternity and paternity confirmed) have been reported for this variant in patients with FPD/AML phenotype.
PS3
No variant-specific functional data (transactivation assays or secondary functional assays) are available for p.Met418Leu.
PS4
No probands meeting RUNX1-phenotypic criteria have been specifically reported for this variant.
PM1
Residue 418 (Met418) lies in the C-terminal region of RUNX1, well outside the Runt homology domain (RHD, residues 89–204) for which the MM-VCEP defines PM1 applicability.
PM2
The variant is present in gnomAD v4.1 with a grpmax filtering allele frequency of 0.004329 (0.43%) and an East Asian AF of 0.005069 (0.51%), far exceeding the MM-VCEP PM2_supporting threshold of ≤0.00005 (0.005%).
PM5
No different missense changes at residue 418 have been established as pathogenic or likely pathogenic in ClinVar.
PM6
No assumed de novo occurrences (without confirmation of maternity and paternity) have been reported for this variant in patients with FPD/AML phenotype.
PP1
No co-segregation data are available.
PP3
REVEL score is 0.219 (threshold ≥0.88 required) and SpliceAI max delta is 0.00 (threshold ≥0.38 required).
Benign
BS1
BS1 is superseded by BA1.
BS3
No functional data demonstrating normal transactivation activity (80–115% of wild-type) are available for this variant.
BS4
No non-segregation data are available.
BP2
No evidence that this variant has been observed in trans with a pathogenic RUNX1 variant or in cis with a pathogenic variant.
N/A · 8
PVS1 · PP2 · PP4 · PP5 · BS2 · BP1 · BP5 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.00140622; MAF= 0.14062%, 1855/1319142 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00506901; MAF= 0.50690%, 119/23476 alleles, homozygotes = 0); grpmax FAF= 0.00432937.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.14%
· 1855 / 1,319,142
0 hom · FAF 0.43%
0 hom · FAF 0.43%
East Asian 119 / 23,476 |
0.51% |
Ashkenazi Jewish 100 / 22,384 |
0.45% |
Remaining individuals 170 / 47,510 |
0.36% |
Middle Eastern 9 / 5,000 |
0.18% |
African/African American 101 / 66,194 |
0.15% |
European (non-Finnish) 1266 / 987,820 |
0.13% |
Admixed American 50 / 45,148 |
0.11% |
European (Finnish) 19 / 39,642 |
0.048% |
South Asian 21 / 81,118 |
0.026% |
+ 1 not observed (Amish)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Benign by ClinGen Myeloid Malignancy Variant Curation Expert Panel (expert panel). (ClinVarID = 1703790)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.219. BayesDel score = -0.190388.
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 not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 2 PMIDs 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