Variant classification summary

NM_001001890.2:c.30C>T

RUNX1 · NP_001001890.1:p.(Ser10=) · NM_001001890.2

GRCh37: chr21:36259380 G>A · GRCh38: chr21:34887083 G>A

Gene: RUNX1 Transcript: NM_001001890.2

Final call

VUS

PM2 supporting BP4 supporting benign BP6 supporting benign BP7 supporting benign

Variant details

Gene

RUNX1

Transcript

NM_001001890.2

Protein

NP_001001890.1:p.(Ser10=)

gnomAD AF

6.256788615647978e-07 (v4.1)

ClinVar

Likely Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_001001890.2:c.30C>T (p.Ser10=) is a synonymous variant in exon 1 of RUNX1. SpliceAI predicts no significant splicing impact (max delta 0.03), supporting BP4 and BP7 at the supporting benign level per the RUNX1 MM-VCEP v3.1.0.

2

In gnomAD v4.1, c.30C>T is observed at an extremely low frequency (1/1,598,264 alleles; AF=6.26e-7), well below the VCEP PM2_Supporting threshold of ≤0.00005. All subpopulations satisfy the threshold, and the variant is absent from gnomAD v2.1.

3

ClinVar reports c.30C>T as Likely Benign, with expert panel review status from the ClinGen Myeloid Malignancy Variant Curation Expert Panel. No contradictory evidence supporting pathogenicity was identified in verified publications.

4

No functional studies, de novo occurrences, proband case data, or segregation evidence for c.30C>T were identified in any verified publication. All ClinVar-linked PMIDs are about unrelated topics (newborn screening policy statements) and do not mention RUNX1 or this variant.

5

Applying the RUNX1 MM-VCEP v3.1.0 point-based classification framework (Tavtigian et al. 2020): PM2_Supporting (+1), BP4 (-1), BP7 (-1). Total score: -1. This falls in the Likely Benign range (-6 to -1).

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework yields a total score of 1, which maps to VUS 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	NM_001001890.2:c.30C>T is a synonymous variant (p.Ser10=) in exon 1 and does not meet any null-variant criterion (nonsense, frameshift, canonical ±1,2 splice) under the RUNX1 MM-VCEP PVS1 decision tree or generic ClinGen SVI PVS1 recommendations.	cspec pvs1_generic_framework
PS1	N/A	Synonymous variant (p.Ser10=) does not change the amino acid; PS1 requires the same amino acid change as a known pathogenic variant.	cspec
PS2	Not met	No proven de novo occurrence of c.30C>T (with both maternity and paternity confirmed) in a patient with FPD/AML phenotype has been identified in any verified publication.
PS3	Not met	No functional assay (transactivation, minigene splicing, or secondary assay) specifically assessing c.30C>T has been identified. Computational predictions (SpliceAI max delta 0.03) are not sufficient to meet PS3.	spliceai
PS4	Not met	No probands meeting RUNX1-phenotypic criteria have been identified in any verified publication specifically reporting c.30C>T. All ClinVar-linked publications are about unrelated topics (newborn screening policy statements) and do not mention RUNX1 or this variant.
PS5	N/A	Under the RUNX1 MM-VCEP v3.1.0, the PP5/PS5 criterion is explicitly marked Not Applicable for this VCEP per ClinGen SVI VCEP Review Committee recommendation.	cspec
PM1	Not met	c.30C>T is at codon 10 in the N-terminal region, outside the Runt homology domain (aa 50-177) and outside the VCEP-defined functionally critical residues (aa 89-204 in the RHD). No mutational hotspot has been established at this position.	cspec
PM2	Met	The variant is extremely rare in population databases. In gnomAD v4.1, the minor allele frequency is 6.26e-7 (0.00006%) with 1 allele observed across 1,598,264 alleles, well below the VCEP PM2_Supporting threshold of ≤0.00005. GrpMax FAF is unavailable; all subpopulations satisfy the PM2_Supporting threshold. The variant is absent from gnomAD v2.1.	gnomad_v4 gnomad_v2 cspec
PM5	N/A	PM5 requires a missense change at the same residue as a known pathogenic missense variant. c.30C>T is a synonymous variant (p.Ser10=) with no amino acid change; the variant class is not missense-like. The PM5 candidate assessment confirms no eligibility.	pm5_candidates cspec
PM6	Not met	No assumed de novo occurrences of c.30C>T (without confirmation of maternity and paternity) in patients with FPD/AML phenotype have been identified in any verified publication.
PP1	Not met	No co-segregation data (meioses observed within families with FPD/AML) has been identified for c.30C>T in any verified publication.
PP2	N/A	PP2 is marked Not Applicable by the RUNX1 MM-VCEP v3.1.0.	cspec
PP3	Not met	For synonymous variants, the RUNX1 VCEP requires SpliceAI ≥ 0.38 for PP3. SpliceAI max delta score is 0.03, well below the threshold. REVEL is not available for this synonymous variant. No computational evidence supports a deleterious effect.	spliceai cspec
PP4	N/A	Under the RUNX1 MM-VCEP v3.1.0, PP4 is marked Not Applicable because the FPD/AML phenotype is not sufficiently specific for a single genetic etiology.	cspec
PP5	N/A	Under the RUNX1 MM-VCEP v3.1.0, PP5 is explicitly marked Not Applicable for this VCEP per ClinGen SVI VCEP Review Committee recommendation.	cspec
BA1	Not met	The RUNX1 VCEP BA1 threshold requires MAF ≥ 0.0015 (0.15%) in any general continental population dataset with ≥2,000 alleles and ≥5 alleles. The highest observed subpopulation frequency is 8.48e-7 (0.000085%) in European (non-Finnish) with only 1 allele observed, far below the BA1 threshold.	gnomad_v4 cspec
BS1	Not met	The RUNX1 VCEP BS1 threshold requires MAF between 0.00015 (0.015%) and 0.0015 (0.15%) in any population dataset with ≥2,000 alleles and ≥5 alleles. The gnomAD v4.1 total AF is 6.26e-7 (0.00006%) with 1 allele observed, below the BS1 lower bound.	gnomad_v4 cspec
BS2	N/A	BS2 is marked Not Applicable by the RUNX1 MM-VCEP v3.1.0.	cspec
BS3	Not met	No functional study (transactivation assay demonstrating normal function, or secondary assay showing normal function) specifically evaluating c.30C>T has been identified. In silico predictions alone do not qualify for BS3.
BS4	Not met	No verified observation of c.30C>T failing to segregate with disease in ≥2 informative meioses has been identified. Claims from the exploratory search attributing segregation data to specific publications could not be confirmed on full-text review; the cited PMIDs are about unrelated topics (newborn screening policy) and do not mention RUNX1 or this variant.
BP1	N/A	BP1 is marked Not Applicable by the RUNX1 MM-VCEP v3.1.0.	cspec
BP2	Not met	No observation of c.30C>T in trans with a known pathogenic RUNX1 variant has been identified. No homozygous state reported in individuals without FPD/AML phenotype.
BP4	Met	For synonymous variants, the RUNX1 VCEP applies BP4 when SpliceAI ≤ 0.20. SpliceAI max delta score for c.30C>T is 0.03, well below the 0.20 threshold, predicting no impact on splicing. REVEL is not applicable for this synonymous variant.	spliceai cspec
BP5	N/A	BP5 is marked Not Applicable by the RUNX1 MM-VCEP v3.1.0.	cspec
BP6	Met	Expert panel ClinGen Myeloid Malignancy Variant Curation Expert Panel classified as Likely benign.	cspec clinvar
BP7	Met	c.30C>T is a synonymous variant in exon 1 at CDS position 30, located 240 nucleotides upstream of the exon 1 donor splice site (c.270). It is not within the last 3 nucleotides preceding a canonical donor or the first nucleotide following a canonical acceptor. SpliceAI max delta is 0.03, well below the VCEP BP7 threshold of ≤0.20. The variant meets all BP7 criteria under the RUNX1 VCEP.	spliceai cspec
BP3	N/A	Skipped per instruction. In-frame indel criterion, not applicable to a substitution variant.
PM3	N/A	Skipped per instruction. RUNX1-associated disorders are autosomal dominant; PM3 applies to recessive disorders.
PM4	N/A	Skipped per instruction. PM4 applies to in-frame deletions/insertions and stop-loss variants; c.30C>T is a synonymous substitution.

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