Annotating and prioritizing genomic variants using the Ensembl Variant Effect Predictor-A tutorial

Abstract

The Ensembl Variant Effect Predictor (VEP) is a freely available, open-source tool for the annotation and filtering of genomic variants. It predicts variant molecular consequences using the Ensembl/GENCODE or RefSeq gene sets. It also reports phenotype associations from databases such as ClinVar, allele frequencies from studies including gnomAD, and predictions of deleteriousness from tools such as Sorting Intolerant From Tolerant and Combined Annotation Dependent Depletion. Ensembl VEP includes filtering options to customize variant prioritization. It is well supported and updated roughly quarterly to incorporate the latest gene, variant, and phenotype association information. Ensembl VEP analysis can be performed using a highly configurable, extensible command-line tool, a Representational State Transfer application programming interface, and a user-friendly web interface. These access methods are designed to suit different levels of bioinformatics experience and meet different needs in terms of data size, visualization, and flexibility. In this tutorial, we will describe performing variant annotation using the Ensembl VEP web tool, which enables sophisticated analysis through a simple interface.

Keywords: VEP; filtering; variant annotation; variant prioritisation; “molecular consequence”.

Figure 1. The Ensembl VEP web interface showing species/assembly selection, data input, transcript set selection, and additional groups of configuration options

Figure 2. The “Identifiers” section, which allows the selection of gene, protein, and HGVS identifiers

Figure 3. The “Variants and frequency data” section, which allows the selection of information known about variants at the same location

Figure 4. The “Additional annotations” section, which allows the selection of transcript, protein domain, regulatory region, and phenotype annotations

Figure 5. The “Predictions” section, which allows the selection of different pathogenicity, splicing, and conservation predictions

Figure 6. Filtering and advanced options

Figure 7. The results page with summary statistics and options for filtering and downloading the results table

Figure 8. The results table showing predicted molecular consequences and links to the location and overlapping genes and variant displays within the Ensembl genome browser

Figure 9

Results table for example input VCF file showing predicted molecular consequences and links to the location, gene, and variant tabs within the Ensembl genome browser for overlapping features as well as SIFT and PolyPhen-2 predictions and allele frequencies for continental populations for the 1000 Genomes project. VCF, variant call format

Figure 10

Results table for example input VCF file showing clinical significance, associated PubMed IDs, and associated phenotypes. VCF, variant call format