VAR-MD

VAR-MD has been designed to optimize annotation for Mendelian inherited disorders. It analyzes variants derived from whole genome or whole exome sequencing data coming from pedigrees. It outputs a list of putative pathogenic mutations based on inheritance models, genotype quality and allele frequency.

VARIANT

VARIANT (VARIant ANalysis Tool) is a web-based tool that interrogates several different databases in parallel. It utilizes dbSNP, 1000 Genomes, the GWAS catalog, OMIM and COSMIC.

VAT

VAT (Variant Analysis Tool) annotates variants which have been mapped on a transcript by the variant calling. It has been extensively used in the 1000 Genomes Project to annotate loss-of-function variants. Of note, together with ANNOVAR, VAT is the only annotation software that is capable of handling structural variations (e.g. large deletions/duplications).

VAAST

VAAST (Variant Annotation Analysis and Search Tool) uses an algorithm which is based on existing information on pathogenic variants to output a likelihood of pathogenicity. Differently from other software, it can also make predictions on non-coding variants.

SEATTLESEQ

SeattleSeq is a platform that integrates the output from other programs and databases to produce predictions on novel and known SNPs. It gives conservation scores, HapMap frequencies, Polyphen predictions and clinical associations. Its computations are also based on dbSNP via the Genome Variation Server.

SNPeffect

This software was designed to make predictions on mutations falling within coding regions. It relies on the information contained in UniProtKB, where there are currently data on more than 60,000 variant proteins. The software utilizes different algorithms like TANGO (which detects regions prone to aggregation), WALTZ (which calculate the propensity of a certain region to produce amyloids) and LIMBO (which predicts chaperone binding sites for the Hsp70 chaperones).

snpEFF

snpEFF is an open source software which can be used to rapidly categorize single nucleotide polymorphisms (SNPs), insertions, and deletions. The Java-based program works with VCF files, it is GATK compatible and returns results of high, medium or low functional impact.

VARIBENCH

VariBench is based on datasets of experimentally validated variations, against which variants can be compared to make predictions. The datasets of VariBench are compiled based on published literature and other public databases. The datasets are categorized in four sections:

1. Variants that affect protein tolerance.

2. Variants that affect protein stability.

3. Variants that affect transcription binding sites.

4. Variants that affects splicing sites (this section is actually very limited, as it containes information on just a couple of genes).

VariBench can also map variants to the sequences contained in RefSeq and within the 3D protein structures at Protein Data Bank (PDB).

POLYPHEN/POLYPHEN2

Polyphen, now available in its version Polyphen2, predicts the impact of a missense mutation based on (1) protein sequence (2) phylogenetic information and (3) structural information. The software actually looks if the mutation is falling within a protein domain essential for the binding to other molecules of for the formation of the secondary/tertiary structure. In particularly Polyphen2 looks at putative disulfide bonds, active sites, binding sites and transmembrane domains and makes computations on 3D models of the protein structure. Polyphen2 also looks at homologous proteins to see if the identified missense mutation has been observed in other proteins of the same family.

PROVEAN

PROVEAN (PROtein Variation Effect ANalyzer) is an in-silico analysis tool to predict whether a missense mutation or an indel has an impact on the biological function of a protein. Like SIFT, PROVEAN is hosted by the J Craig Venter Institute, where they claim its output to be comparable  to the one of other software like Polyphen2 or SIFT.

A variant of the software called PROVEAN HUMAN GENOME VARIANTS returns the results of PROVEAN and SIFT simultaneously.

SIFT

SIFT (Sorting Tolerant From Intolerant)

SIFT is an in-silico analysis tool that predicts pathogenicity based on the level of conservation of an amino acid residue across different species. The assumption is that residues which are essential for protein function must be highly conserved and that mutations affecting such residues are therefore highly likely pathogenic.

The SIFT homepage is hosted by the J Craig Venter Institute, where also the PROVEAN tool is available.