Variant

Common and rare variation in Open Targets Platform

Overview

In the Open Targets Platform, a variant refers to any human variation associated with a disease, trait or phenotype that has been reported in any of our sources. All variation is mapped to GRCh38 build and enriched with functional annotation. The Platform currently captures single nucleotide polymorphisms (SNPs) and insertions/deletions.

Variant identifier

Variant identifiers of SNPs and small indels are created based on genomic location and alleles like: 6_160589086_A_G where A is the reference allele at position 160,589,086 on chromosome 6 and the alternate allele is G. Being consistent with gnomAD, we are using a 1-based coordinate system.

For longer insertions (200+) and deletions, where keeping the full length of the allele in the variant identifier is impractical, the allele string is hashed to create the identifier, which, when available, might contain the chromosome and position as well. Example: OTVAR_11_614383_9cc2ae367cc98c283cb510e8ea29c9f0

All variants shown in the Platform are reported in at least one of our variant-to-phenotype sources.

Population Allele Frequencies

Alternate allelic frequencies from gnomAD variation database are reported for all major populations when available.

Source: gnomAD 4.1

Variant effect

Variants are annotated with an integrated view of variant effects from multiple methods. Based on all predictions or annotations, we normalise the variant's likely deleteriousness to a common scale.

To make the predicted variant effects comparable across different methods, raw predictions from each methods were normalised to a unified scale ranging from likely benign to uncertain to likely deleterious.

Molecular Structure Viewer

For predicted missense variants, we have included a Molecular Structure Viewer on the variant page, with the reference amino acid highlighted within the AlphaFold predicted model for the relevant protein.

The feature includes the option to visualise:

1. Protein pathogenicity - highlighting the AlphaMissense pathogenicity for the substitution corresponding to the variant, and the average AlphaMissense pathogenicity score across all possible amino acid substitutions at other positions

2. Protein domains (from Uniprot)

3. Secondary structure (from AlphaFold)

4. Residues hydrophobicity (from here)

The widget also includes a linear representation of the protein which updates alongside the structural representation.

You can take a look at this example view for variant 7_44152420_C_G to discover more about scores and colour coding used to build the viewer.

Source: AlphaPhold DB, UniProt

Transcript consequences

Every variant is annotated with the predicted consequence for all canonical transcripts in a +/-500Kb window, allowing us to understand the likely effects in the neighbouring coding or non-coding genes. For all variant-transcript pairs in the region, this information includes:

• Distance from transcription start site (TSS)

• Distance to footprint

• Predicted functional consequence based on Ensembl VEP

• Amino-acid consequence relative to the UniProt reference protein

Source: Ensembl VEP

Variant-to-phenotype

The list of variant sources includes:

• 95% GWAS credible sets

• 95% Molecular QTL credible sets

• Enhancer-to-gene: Epigenetically derived genomic regions that regulate putative genes.

• ClinVar: Submitted variants at all clinical significances

• Uniprot: Literature-based curation of disease-associated variants

• Pharmacogenetics: Variants corresponding to genotypes associated with drug responses