Variant classification summary

NM_001754.4:c.1270T>G

RUNX1 · NP_001745.2:p.(Ser424Ala) · NM_001754.4

GRCh37: chr21:36164605 A>C · GRCh38: chr21:34792308 A>C

Gene: RUNX1 Transcript: NM_001754.4

Final call

Benign

BA1 stand-alone benign BP4 supporting benign

Variant details

Gene

RUNX1

Transcript

NM_001754.4

Protein

NP_001745.2:p.(Ser424Ala)

gnomAD AF

0.0027401133863950203 (v4.1)

ClinVar

Uncertain Significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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.

4

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.

5

A single somatic occurrence has been reported in COSMIC (COSV99038603, n=1), which is not sufficient to support pathogenicity in the germline context.

6

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.

Final determination: ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RUNX1 Version 3.1 v3.1 point-based framework yields a total score of -9, which maps to Benign under the specified Tavtigian-style ranges.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Missense variant (p.Ser424Ala); not a null variant. RUNX1 VCEP PVS1 decision tree applies only to nonsense, frameshift, canonical splice, and initiation codon variants.	pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No prior classification of the same amino acid change (p.Ser424Ala) as pathogenic or likely pathogenic exists. Only one nucleotide change (c.1270T>G) produces S424A, and it is classified as VUS in ClinVar.	clinvar pm5_candidates
PS2	Not met	No de novo occurrence data available in the literature or ClinVar. Neither confirmed nor assumed de novo reports were identified for this variant.	clinvar
PS3	Not met	No variant-specific functional data identified. OncoKB reports unknown oncogenic effect with no curated functional PMIDs. No transactivation assay, secondary assay, or systematic range characterization data available for p.Ser424Ala.	oncokb
PS4	Not met	No probands meeting RUNX1-phenotypic criteria (FPD/AML) identified in the available evidence. The variant is present in gnomAD at 0.27% overall frequency, and no case-level data was found in publications or ClinVar submissions beyond general citations to ACMG guidelines.	clinvar gnomad_v4
PS5	Not met	No reputable source reports this variant as pathogenic. ClinVar classification is Uncertain Significance by the ClinGen Myeloid Malignancy VCEP. PS5/PP5 are not applicable under the VCEP specification; assessed under generic ACMG/AMP rules — not met.	clinvar
PM1	Not met	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. Not in a VCEP-defined critical functional domain.	cspec
PM2	Not met	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). Absent from gnomAD v2.1, but v4.1 data supersedes.	gnomad_v2 gnomad_v4
PM5	Not met	No other missense variants at codon 424 classified as pathogenic or likely pathogenic identified in ClinVar. No same-residue comparator variants available to support PM5.	pm5_candidates clinvar
PM6	Not met	No assumed or confirmed de novo occurrences identified. No reports of this variant arising de novo in patients with FPD/AML phenotype.	clinvar
PP1	Not met	No co-segregation data available. No family studies or meioses counts reported for this variant.
PP2	N/A	VCEP specification: PP2 is Not Applicable for RUNX1.	cspec
PP3	Not met	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. Computational predictors do not support a damaging effect.	revel spliceai bayesdel
PP4	N/A	VCEP specification: PP4 is Not Applicable for RUNX1. FPD/AML phenotype is not sufficiently specific for a disease with a single genetic etiology.	cspec
PP5	N/A	VCEP specification: PP5 is Not Applicable as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Met	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.	gnomad_v4
BS1	Not met	The variant allele frequency (EAS 1.05%, overall 0.27%) exceeds the BS1 range of 0.015%–0.15%. The variant qualifies for BA1 (stand-alone benign), which supersedes BS1.	gnomad_v4
BS2	N/A	VCEP specification: BS2 is Not Applicable for RUNX1.	cspec
BS3	Not met	No functional studies demonstrating normal RUNX1 transactivation (80–115% of wild-type) identified. No transactivation assay or secondary assay data available for p.Ser424Ala.	oncokb
BS4	Not met	No segregation data available to assess lack of segregation in affected families. No informative meioses data reported.
BP1	N/A	VCEP specification: BP1 is Not Applicable for RUNX1.	cspec
BP2	Not met	No evidence of this variant occurring in trans with a known pathogenic RUNX1 variant or in a homozygous state in unaffected individuals.
BP4	Met	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 spliceai bayesdel
BP5	N/A	VCEP specification: BP5 is Not Applicable for RUNX1.	cspec
BP6	N/A	VCEP specification: BP6 is Not Applicable as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	BP7 applies only to synonymous and intronic variants with SpliceAI ≤0.20. This is a missense variant (c.1270T>G, p.Ser424Ala) and is not eligible for BP7.	cspec

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