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Background As NGS has become more widely used in the diagnosis of rare diseases, an increasing number of variants of uncertain significance (VUS) have been detected, and their interpretation remains challenging. In particular, when a LOF variant in a non-conserved exon of the MANE transcript is detected by ES, yet the individual carrying this variant exhibits no clinical manifestations. In this context, the ACMG Splicing Subgroup introduced the term 'rescue transcripts' to guide the interpretation of LOF variants located within non-conserved exons. Methods In this study, the properties of four different variants were characterised using in silico predictions, protein structural analysis, population frequency data, and clinical observations. Results Three variants (AMMECR1: c. 220CT; GLI2: c. 162₁63delCT; COL11A1: c. 1245+1GA) were reclassified as likely benign (LB) /VUS because rescue transcripts were identified in the corresponding genes. Another variant (EHMT1: exon2-10 del) was reclassified as a VUS, as exons 2-10 may represent non-constitutive exons, and the deletion (p. 8A–549E del) may not affect protein function. Therefore, this variant should not be assigned a PVS1 code. Conclusion The presented case studies provide actionable recommendations for identifying rescue transcripts and enhance the understanding of the correct application of PVS1 codes.
Leng et al. (Wed,) studied this question.