NM_005089.3:c.398_399del is a frameshift variant in exon 5 of ZRSR2 predicted to cause premature termination at codon 143 (p.Glu133GlyfsTer11), resulting in loss of approximately 70% of the protein including functionally critical zinc finger and RS-rich domains.¹ ZRSR2 loss-of-function is an established germline disease mechanism: germline ZRSR2 mutations cause oral-facial-digital syndrome (PMID:38158857) and have been reported in constitutional aplastic anemia (PMID:35371815). ZRSR2 is a core component of the minor (U12) spliceosome, and its depletion causes widespread U12-type intron retention (PMID:25586593).² Under the ClinGen SVI PVS1 decision framework (PMC6185798), a frameshift variant in a gene with an established LOF disease mechanism is classified as PVS1 at very_strong strength. NMD is predicted as the premature termination codon occurs in exon 5 of 11.³ The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, supporting PM2 at moderate strength (allele frequency <0.1% per generic ACMG thresholds).⁴ The variant has been observed once in a somatic cancer sample (COSMIC COSV57067023), consistent with its predicted loss-of-function effect, though this somatic observation is not directly applied to germline ACMG criteria. No variant-specific functional studies, de novo observations, segregation data, or ClinVar classifications were identified for this variant.⁵ Combined evidence: 1 Very_Strong (PVS1) + 1 Moderate (PM2) meets the generic ACMG/AMP Likely Pathogenic classification threshold (1 Very_Strong + 1 Moderate).⁶