Fig. 4

Splicing constraint for pathogenic alternative splicing variants. A Regional constraint profile for the ACVRL1 gene with pathogenic splice-altering variants that cause HHT. The pathogenic variants are labeled as orange lollipops on the gene track and the corresponding splicing constraint region is circled in orange on the ConSplice track. The ConSplice score is provided below the variant lollipop. The y-axis depicts the regional constraint score log10 scale. B-C Zoomed-in view of the genomic regions that harbor the pathogenic variants in ACVRL1 seen in A. D The distribution of the manually curated pathogenic variants relative to the exonic position. The blue bar represents an exon while the gray bars represent introns around the exon. Oriented 5′ to 3’ from left to right, with the acceptor side on the left and the donor side on the right. Any variant > 10 bp away from the exon–intron junction in the intron or exon are labeled “Deep Intronic” or “Deep Exonic”, respectively. Canonical acceptor and donor sites = A-1, A-2., D + 1, D + 2. E The distribution of scores assigned by each method to the pathogenic variants in the set. The IQR of the boxes ranges from the 25th to 75th percentile. The vertical black line in each box represents the median score for that method. The whiskers are 1.5X the IQR. Outliers are not plotted