NM_001001890.2:c.624C>T (p.Ala208=) is a synonymous variant in exon 4 of RUNX1 that does not alter the amino acid sequence.

This variant is present at extremely low frequency in gnomAD (v4.1 grpmax FAF = 3.259e-05, 53/1,613,324 alleles), meeting PM2_Supporting under the MM-VCEP specification (MAF ≤0.00005).

SpliceAI predicts no splice impact (max delta = 0.02), meeting BP4 (SpliceAI ≤0.20 for synonymous variants) under the MM-VCEP specification.

The variant meets BP7 as a synonymous change not located in the critical splice region (not in the last 3 nucleotides of exon 4 nor the first nucleotide after the acceptor site), with SpliceAI ≤0.20.

The ClinGen Myeloid Malignancy VCEP classified this variant as Likely Benign (ClinVar ID 532686, SCV001366061, reviewed by expert panel), consistent with the computed Tavtigian score of -1 (PM2_Supporting +1, BP4 -1, BP7 -1).

No pathogenic evidence was identified: no de novo occurrences (PS2/PM6), no probands with FPD/AML phenotype (PS4), no functional data demonstrating damaging effect (PS3), no cosegregation data (PP1), the variant lies outside the RHD (PM1 not met), and in silico predictions do not support pathogenicity (PP3 not met).

Population frequencies are too low to meet BA1 (>0.15%) or BS1 (0.015%-0.15%), but the variant is not absent from population databases.

BS3 could not be independently assessed as the primary functional assay data reviewed by the expert panel is not publicly accessible through ClinVar; however, the expert panel's Likely Benign classification implies functional evidence was not supportive of pathogenicity.