Fig. 2

X-CAP features show predictive power. Comparison of feature values for benign and pathogenic stopgains in the training set of \(\mathcal {D}_{\text {original}}\). a The Residual Variation Intoleration Score (RVIS) decile of genes, weighted by the number of variants they contain. Genes without RVIS values were excluded. Pathogenic variants are more prevalent in low RVIS genes, namely those generally intolerant to variation. b Kernel Density Estimation (KDE) plot of the relative variant location, defined as the distance in the coding domain sequence (CDS) from the translation start site divided by the total CDS length. On average, benign stopgains are located later in transcripts than pathogenic stopgains. c KDE plot of the number of exons in the mutated gene. The maximum number of exons is clipped to 100 for clarity. Genes containing benign stopgains tend to have fewer exons than genes containing pathogenic stopgains. d Odds ratios (pathogenic/benign) comparing variants that introduce a given stop codon to those that do not. The TGA stop codon, molecularly shown to be the most amenable to read-through of the three [36], is depleted in pathogenic variants. e Odds ratios comparing 5’ proximal stopgains (those within the first 100 bp of the sequence) that have a potential alternative downstream start codon a given distance away against those that do not. Pathogenic variants tend to be located further from the next downstream start codon than benign variants. f KDE plot of the mean phyloP of the downstream region, the portion of the CDS truncated by the stopgain. Regions downstream of pathogenic variants are more conserved than regions downstream of benign variants. In b, c, and f, Scott’s Rule [52] was used to calculate the bandwidth of the Gaussian kernel. In d and e, error bars denote 95% confidence intervals for the odds ratio