Fig. 3.

NF1-SPRED1 binding region.

SPRED1 interacts with NF1 by binding to the N and C terminal regions of the RAS-GAP domain. The number of codons with at least one variant predicted to be pathogenic by the model (score above 0.538; corresponding to a FPR of 1%) was compared between these putative binding regions and the adjacent regions (100 base pairs on each side) showed an increase in variants predicted to be pathogenic in the N-terminal binding region (OR 2.19; 1.22 to 3.99; P = 0.005) but only a trend in the C-terminal (OR 2.18; 0.9 to 5.1; P = 0.072). Generating a score across all the codons identified a drop in pathogenicity rate beyond codon 1528. The dashed line marks the borders of the known binding region (codons 1176–1248 and 1477–1573 for the N and C terminal regions, respectively) and the solid line marks the borders of regions previously described as essential (Codons 1202–1217 and 1511 and 1530).