Predicted Effects of hTP Variants.

*PolyPhen-2 provides two results based on HumVar (13,032 human disease causing mutations from UniProt and 8,946 human nonsynonymous single-nucleotide polymorphisms (nsSNPs) and HumDiv [29]. These prediction algorithms return a scaled probability from 0 (neutral) to >1 (damaging).†The Grantham score [32] represents the original amino acid substitution scoring method, presenting a scale increasing from zero to indicate the degree of side-chain physicochemical difference between the original and mutant amino acid. Single digit scores are considered conservative, with severe mutations ranging 60 or higher.‡The SIFT (Sorting Intolerant From Tolerant) algorithm (http://blocks.fhcrc.org/sift/SIFT.html) [26] infers functional importance from sequence homology. Based on a PSI-BLAST search alignment, SIFT returns a scaled probability matrix for the likelihood of a protein to tolerate each of the twenty amino acids at each position in the protein. Output values for each amino acid change tolerance from SIFT ranges from 0 (damaging) to 1 (neutral).§ProPhylER (http://www.prophyler.org) [31] combines the physicochemical properties of amino acid side chains and the observed evolutionary variation of those properties to infer deleterious substitutions.║The module of the SNPs3D resource (http://www.SNPs3D.org) [30] which focuses on predicting SNP influence on protein function, separately evaluates protein structural stability analysis and sequence conservation using a support vector machine approach trained on monogenic disease. Negative values are considered deleterious, positive values considered neutral, and values beyond ±0.5 indicate the degree of confidence.#Position specific scoring matrix returns sequence alignment-based probability, with lower scores for damaging variants.