Variant Effect Predictor (VEP) Settings

The Variant Effect Predictor (VEP) is a variant detection and classification algorithm. The VEP prediction is based on the following three factors:

  • The location of the variant in or near a gene

  • The predicted consequence of the variant on protein expression

  • The frequency of the variant in the human population

VEP uses two variant classification systems - SIFT (Sorting Intolerant From Tolerant) and PolyPhen2 (Polymorphism Phenotype) - to score the changes to the protein coding sequence, and generates a variant consequence prediction (VEP consequence). CSA summarizes VEP consequences into four categories of impact, based on the predicted consequence of the variant:

  • HIGH - Protein-truncating variants

  • MODERATE - Missense mutations, inflame indels, and splice-region variants outside the canonical splice site

  • LOW - Lower impact variants

  • LOWEST - Lowest impact variants

If a variant has more than one impact annotation in different transcripts, CSA reports the most severe or maximum impact notation. The full set of VEP consequences are available in Sequence Miner.

Note

Variants whose VEP consequence is classified as HIGH are protected from filtering in the Candidate genes and All variants tabs in the Advanced report view.

The figure below details the types of variants and the impact category to which they belong:

../_images/vepConsequence.png

VEP variant consequences and their location in a transcript

VEP impact, VEP predicted consequence, and a translation of how to interpret the designated classes of variants are described in the following table:

Variant consequences and descriptions

Impact

Consequence

Description

HIGH

transcript_ablation

A feature ablation where the deleted region includes a transcript feature

HIGH

splice_acceptor_variant

A splice variant that changes the 2 base region at the 3’ end of an intron

HIGH

splice_donor_variant

A splice variant that changes the 2 base region at the 5’ end of an intron

HIGH

stop_gained

A sequence variant where at least one base in a codon is changed, resulting in a premature stop codon that leads to a shortened transcript

HIGH

frameshift_variant

A sequence variant that causes a disruption in the translational reading frame because the number of nucleotides inserted or deleted is not a multiple of three

HIGH

stop_lost

A sequence variant where at least one base in the terminator codon (stop) is changed, resulting in an elongated transcript

HIGH

start_lost

A codon variant that changes at least one base in the initiator codon of a transcript

HIGH

transcript_amplification

A feature amplification of a region containing a transcript

MODERATE

inframe_insertion

An in-frame non-synonymous variant that inserts bases into a coding sequence

MODERATE

inframe_deletion

An in-frame non-synonymous variant that deletes bases from a coding sequence

MODERATE

missense_variant

A sequence variant that changes one or more bases, resulting in a different amino acid sequence and preserving the length of the transcribed protein

MODERATE

protein_altering_variant

A sequence variant which is predicted to change the protein encoded in the coding sequence

MODERATE

splice_region_variant

A sequence variant where a change has occurred within the region of the splice site within 1-3 bases of an exon or 3-8 bases of an intron

MODERATE

incomplete_terminal_codon_variant

A sequence variant where at least one base in the final codon of an incompletely annotated transcript is changed

LOW

stop_retained_variant

A sequence variant where at least one base in the terminator codon is changed but the terminator remains

LOW

synonymous_variant

A sequence variant where there is no resulting change in the encoded amino acid

LOW

coding_sequence_variant

A sequence variant that changes the coding sequence

LOW

mature_miRNA_variant

A transcript variant located with the sequence of a mature miRNA

LOW

5_prime_UTR_variant

A UTR variant in a 5’ UTR

LOW

3_prime_UTR_variant

A UTR variant in a 3’ UTR

LOW

non_coding_transcript_exon_variant

A sequence variant that changes a non-coding exon sequence

LOW

intron_variant

A transcript variant occurring within an intron

LOW

NMD_transcript_variant

A variant in a transcript that is the target of Nonsense-mediated mRNA decay (NMD)

LOWEST

non_coding_transcript_variant

A non-coding RNA transcript variant

LOWEST

upstream_gene_variant

A sequence variant located in the 5’ upstream region of a gene

LOWEST

downstream_gene_variant

A sequence variant located in the 3’ downstream region of a gene

LOWEST

TFBS_ablation

A feature ablation where a deleted region includes a transcription factor binding site

LOWEST

TFBS_amplification

A feature amplification in a region containing a transcription factor binding site

LOWEST

TF_binding_site_variant

A sequence variant located in a transcription factor binding site

LOWEST

regulatory_region_ablation

A feature ablation where a deleted region includes a regulatory region

LOWEST

regulatory_region_amplification

A feature amplification of a region containing a regulatory region

LOWEST

feature_elongation

A sequence variant that leads to the extension of a genomic feature with regards to the reference sequence

LOWEST

regulatory_region_variant

A sequence variant located within a regulatory region

LOWEST

feature_truncation

A sequence variant that leads to the reduction of a genomic feature with regards to the reference sequence

LOWEST

intergenic_variant

A sequence variant located in the intergenic region between genes

LOWEST

intergenic_variant

A sequence variant located in the intergenic region between genes

LOWEST

regulatory_region_fusion

A feature fusion where the deletion brings together regulatory regions

LOWEST

regulatory_region_translocation

A feature translocation where the region contains a regulatory region

LOWEST

TFBS_fusion

A fusion where the deletion brings together transcription factor binding sites

LOWEST

TFBS_translocation

A feature translocation where the region contains a transcription factor binding site

References