As previously alluded to, FATHMM not only predicts the potentially deleterious nature of AASs but is also capable of annotating the molecular and phenotypic consequences of these mutations via domain-centric ontologies. To illustrate this, we evaluated the predicted phenotypic consequences of disease-associated AASs within the SwissVar dataset (Supp. Table S4). As expected, the phenotypic consequences of well-characterized diseases are correctly identified. For example, the cardiovascular consequences of the C1971Y mutation in FBN1 (Marfan syndrome; MIM# 154700) are correctly identified via domain-based ontological associations. However, potential issues of using domain-centric ontologies arise when a common domain harbors multiple mutations with distinct and uniquely expressed phenotypes. In these instances, domain-centric ontological associations may have become diluted and should therefore be used with caution. For example, the predicted phenotypic consequences for the R239C mutation in CHRNG (Escobar syndrome; MIM# 265000) are consistent with the associated syndrome, which is characterized by a decrease in fetal movement and overall muscle weakness. However, phenotypes not associated with (or secondary to) Escobar syndrome, for example abnormalities in temperature regulation, were also predicted. Nevertheless, we foresee that these annotations will be most prominent in protein sequences of unknown function and/or ongoing nonhuman genome sequencing projects, as demonstrated below.
