Fig. 2: Pathogenic and benign variation, missense constraint and evolutionary conservation in ABL1 (NM_007313.2).

a Pathogenic and benign variants in ABL1. Red points indicate pathogenic germline ABL1 variants described here and previously. Blue points indicate non-pathogenic ABL1 missense variants in DECIPHER. Yellow points indicate somatic missense variants in haematological malignancy associated with Tyrosine Kinase Inhibitor (TKI) resistance in the COSMIC database. Raised yellow points indicate that this variant is also seen in the germline in a DECIPHER participant. Grey points indicate missense variants in gnomAD. b Schematic of functional domains in ABL1, with amino acid residue labelled on the horizontal axis. Pathogenic missense variants cluster near the kinase domain of the transcript, as do somatic missense variants conferring resistance to imatinib. The kinase domain is also depleted for non-pathogenic variants in DECIPHER, and for benign variation in gnomAD. c Missense constraint in ABL1. Moving average of Missense Tolerance Ratio (MTR) scores with 20 codon window. MTR scores represent the missense tolerance of ABL1 codons, derived from the prevalence of missense variation in the ExAC cohort. Lower scores indicate codons which are under missense constraint. Codons in the kinase domain and SH3/2 domains are under greater missense constraint than the remainder of the transcript. d Basewise conservation in ABL1. Moving average of basewise PhyloP scores with 60 base window. Higher scores indicate more highly conserved bases. Bases at the 5′ end of the transcript, comprising the SH3, SH2, and kinase domains, tend to be more highly conserved than the remainder of the transcript.