Variant classification summary

NM_001754.4:c.1265A>C

RUNX1 · NP_001745.2:p.(Glu422Ala) · NM_001754.4

GRCh37: chr21:36164610 T>G · GRCh38: chr21:34792313 T>G

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.(Glu422Ala)

gnomAD AF

0.001745527826418449 (v4.1)

ClinVar

Uncertain Significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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.

4

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.

5

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.

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	Not met	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). Not eligible for PVS1 under the RUNX1 PVS1 decision tree.	pvs1_variant_assessment
PS1	Not met	p.Glu422Ala (E422A) has not been previously established as a pathogenic or likely pathogenic variant by the MM-VCEP. No evidence of the same amino acid change classified as P/LP was identified.	clinvar vcep_myeloid_malignancy_vcep_runx1_pilot_results
PS2	Not met	No de novo occurrence (proven or assumed) was identified for NM_001754.4:c.1265A>C in any reviewed publication or ClinVar submission.
PS3	Not met	No functional studies testing NM_001754.4:c.1265A>C (p.Glu422Ala) or a systematically characterized range including codon 422 were identified. OncoKB reports Unknown Oncogenic Effect for this variant.	oncokb
PS4	Not met	No probands meeting RUNX1-phenotypic criteria were identified for this variant in the reviewed literature or ClinVar submissions.
PS5	N/A	PS5 is not defined in the ClinGen Myeloid Malignancy VCEP RUNX1 specification (v3.1) and is not a standard ACMG/AMP criterion with established rules.
PM1	Not met	The variant p.Glu422Ala lies at codon 422, which is well outside the Runt homology domain (RHD, residues 89-204). PM1 applies only to residues within the RHD per the MM-VCEP specification.	cspec
PM2	Not met	The VCEP PM2_Supporting threshold requires MAF ≤ 0.00005 (0.005%). This variant has a gnomAD v4.1 overall AF of 0.1746% (0.001746) and grpmax FAF of 0.4026% (0.004026), both far exceeding the PM2 threshold.	gnomad_v4
PM5	Not met	No different missense change at codon 422 has been established as pathogenic or likely pathogenic by the MM-VCEP. The ClinVar record for this variant (ID 988848) is classified as Uncertain Significance, and no sister variant at codon 422 was identified in the VCEP pilot results.	clinvar pm5_candidates
PM6	Not met	No assumed de novo occurrences were identified for this variant in any reviewed publication or ClinVar record.
PP1	Not met	No co-segregation data (informative meioses) were identified for this variant in any reviewed publication or case material.
PP2	N/A	Not applicable per the ClinGen Myeloid Malignancy VCEP RUNX1 specification (v3.1).	cspec
PP3	Not met	For missense variants, the VCEP PP3 rule requires REVEL ≥ 0.88 or SpliceAI ≥ 0.38. This variant has REVEL = 0.052 and SpliceAI Δ = 0.00, neither meeting the pathogenic threshold.	revel spliceai bayesdel
PP4	N/A	Not applicable per the ClinGen Myeloid Malignancy VCEP RUNX1 specification (v3.1). The FPD/AML phenotype is not specific enough to meet PP4.	cspec
PP5	N/A	Not for use per the ClinGen Myeloid Malignancy VCEP RUNX1 specification (v3.1), following the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BA1	Met	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%.	gnomad_v4 cspec
BS1	Not met	BS1 is superseded by BA1, which already applies at a higher (stand-alone) strength. The variant's grpmax FAF of 0.4026% exceeds even the BA1 threshold. Applying both BS1 and BA1 would be double-counting the same population evidence.	gnomad_v4
BS2	N/A	Not applicable per the ClinGen Myeloid Malignancy VCEP RUNX1 specification (v3.1). BS2 is not applicable because FPD/AML patients display incomplete penetrance and the average age of onset of hematologic malignancies is 33 years.	cspec
BS3	Not met	No functional studies demonstrating normal transactivation (80-115% of wild-type) or normal function in secondary assays were identified for p.Glu422Ala. OncoKB reports Unknown Oncogenic Effect.	oncokb
BS4	Not met	No segregation data demonstrating lack of segregation in ≥ 2 informative meioses were identified for this variant.
BP1	N/A	Not applicable per the ClinGen Myeloid Malignancy VCEP RUNX1 specification (v3.1).	cspec
BP2	Not met	No evidence of this variant observed in trans with a pathogenic RUNX1 variant or in cis with a pathogenic variant was identified.
BP4	Met	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 spliceai bayesdel
BP5	N/A	Not applicable per the ClinGen Myeloid Malignancy VCEP RUNX1 specification (v3.1). A patient can carry two pathogenic variants in genes predisposing to hematologic malignancies.	cspec
BP6	N/A	Not for use per the ClinGen Myeloid Malignancy VCEP RUNX1 specification (v3.1), following the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BP7	N/A	BP7 applies only to synonymous variants (excluding those near splice sites) and intronic variants with SpliceAI ≤ 0.20. NM_001754.4:c.1265A>C is a missense variant (p.Glu422Ala), not eligible for BP7.	cspec spliceai

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