The impact of transcript alignment on variant interpretation

The problematic gene list can be narrowed to 71 genes for hg79 and 15 genes for hg38 selecting the ones with clinical relevance based on coding transcripts (those with NM_* accession) and the ones associated with phenotypes in the Human Phenotype Ontology (HPO). Analyzing clinical data from allexes®, the reference data network connecting varvis® software setups, reveals that around 1.8% of clinical reports refer to genes with mapping gaps, impacting diagnostics across a significant number of diseases and patient records. Interestingly, these cases aren’t uniformly distributed but rather concentrated on a few transcripts, notably ALMS1 and SHANK3, representing about 45% of the affected cases in hg38 (Figure 2).

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