NM_000022.4(ADA):c.956_960del (p.Glu319Glyfs*3) — also reported as c.955_959delAAGAG in older literature — is a 5-bp deletion in exon 10 causing a frameshift beginning at codon 319 with a premature termination codon predicted 3 residues downstream (~codon 322). This lies well upstream of the ADA-specific NMD-escape anchor at c.1028 (codon 343, exon 11), so the transcript is predicted to undergo nonsense-mediated decay. This prediction is directly supported by experimental data: Gossage et al. 1993 (PMID 8242080) reported a homozygous patient with "very low levels of ADA mRNA and protein," consistent with NMD, and Santisteban et al. 1993 (PMID 8227344) similarly found this deletion associated with severely reduced corresponding transcript levels in a heterozygous carrier (patient MJ). Therefore, PVS1 was met at full strength. The Grpmax filtering allele frequency of this variant is 0.00021203 (Non-Finnish European) in gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, but lower than the BS1 threshold (>0.001611). Therefore, neither criterion is met. At least one proband (P3, Cagdas et al. 2018, PMID 29744787) meets diagnostic criteria for SCID with a T-B-NK- phenotype (0.5 pt); has profoundly reduced ADA enzyme activity, undetectable (0 nmol/h/mg), with elevated dAXP (71.9%) (5.0 pts); and presents with a T-B-NK- lymphocyte subset profile (0.5 pt). Total: 6.0 points, meeting PP4_Strong. In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PP4_Strong (VCEP specifications version 2.2).