Fig. 3

Structural hypotheses about the effects of six segregating RTEL1 VUS. a W512 is predicted to lie on the surface of the protein. A mutation to cysteine has the potential to interfere with functionally important protein-protein interactions. b V516 forms a small well-packed hydrophobic core, which lies under a patch of positively charged surface residues. Mutation to leucine adds steric bulk and may induce structural rearrangements that disrupt DNA binding. c S540 is a polar residue predicted to lie on a surface-exposed alpha helix in the helicase II domain. Mutation to alanine may alter surface charge or cause rotation of the alpha helix. d F559 is buried in the core of the protein, in close proximity to residues predicted to form part of the DNA-binding cavity, including A621 and E591. Mutation to isoleucine removes steric bulk and is likely to leave a void in the hydrophobic core of the protein, disrupting structure and reducing stability. e D719 is predicted to fall in a surface-exposed helix. Mutation to glycine drastically reduces both the bulk and charge of the protein’s surface, and likely disrupts the helix at that point. f T55 is predicted to form part of the interface between helices 1 and 2 in RTEL1. Mutation to a serine would reduce the steric bulk and alter the packing between the two helices