PROVEAN

PROVEAN (Protein Variation Effect Analyzer) is a bioinformatics tool that provides computational predictions for the functional effects of protein sequence variations, which is critical for narrowing down the search for causal variants in disease phenotypes. As next-generation sequencing projects generate massive genome-wide sequence variation data, the need for tools that can analyze the effects of sequence variations on protein function is greater than ever before.

Different sequence variations at the nucleotide level are associated with human diseases, including substitutions, insertions, deletions, frameshifts, and nonsense mutations. Frameshifts and non-sense mutations are likely to cause a negative effect on protein function. However, existing prediction tools primarily focus on studying the deleterious effects of single amino acid substitutions by examining amino acid conservation at the position of interest among related sequences. This approach is not directly applicable to insertions or deletions.

PROVEAN addresses this limitation by introducing a versatile alignment-based score as a new metric to predict the damaging effects of variations not limited to single amino acid substitutions but also in-frame insertions, deletions, and multiple amino acid substitutions. This alignment-based score measures the change in sequence similarity of a query sequence to a protein sequence homolog before and after introducing an amino acid variation to the query sequence.

The Authors’ results have shown that the scoring scheme performs well in separating disease-associated variants from common polymorphisms and deleterious variants from neutral variants. We separated 21,662 disease-associated variants from 37,022 common polymorphisms for UniProt human protein variations. For UniProt non-human protein variations, we separated 15,179 deleterious variants from 17,891 neutral ones. In our approach, the area under the receiver operating characteristic curve (AUC) for the human and non-human protein variation datasets is approximately 0.85.