Hypomorphic alleles pose challenges in rare disease genomic variant interpretation

Exon skipping associated with an ATP7B intronic variant in a patient with Wilson's disease. (A) Sashimi plot visualization of aligned RNA sequencing data from proband liver tissue at ATP7B exons 14‐13‐12. The red track shows traditional RNA‐seq data; the blue track shows RNA‐seq enriched with exon capture (cDNA‐cap) which achieves higher depth of protein‐coding transcripts. The histogram indicates overall sequencing depth while arcs tabulate the number of junction‐spanning reads supporting exon pairs. (B) The domain structure (top) and exon structure (bottom) of ATP7B. Loss of exon 13 (dashed box) would remove a transmembrane domain and disrupt the first phosphorylation domain