Relationship of VRS to existing standards

Because a primary objective of the GA4GH Variation Representation Specification (VRS) effort is to unify disparate efforts to represent biological sequence variation, it is important to describe how this document relates to previous work in order to avoid “reinventing the wheel”.

The Variant Call Format (VCF) is the de facto standard for representing alleles, particularly for use during primary analysis in high-throughput sequencing pipelines. VCF permits a wide range of annotations on alleles, such as quality and likelihood scores. VCF is a file-based format and is exclusively for genomic alleles. In contrast, the VRS data model abstractly represents Alleles, Haplotypes, and Genotypes on all sequence types, is independent of medium, and is well-suited to secondary analyses, allele interpretation, aggregation, and system-level interoperability.

The HGVS nomenclature recommendations describe how sequence variation should be presented to human beings. In addition to representing a wide variety of sequence changes from single residue variation through large cytogenetic events, HGVS attempts to also encode in strings notions of biological mechanism (e.g., inversion as a kind of deletion-insertion event), predicted events (e.g., parentheses for computing protein sequence), and complex states (e.g., mosaicism). In practice, HGVS recommendations are difficult to implement fully and consistently, leading to ambiguity in presentation. In contrast, the VRS is a formal specification that improves consistency of representation among computer systems. VRS is currently less expressive than HGVS for rarer cases of variation, such as cytogenetic variation or context-based allele representations (e.g., insT written as dupT when the insertion follows a T). Future versions of the specification will seek to address limitations while preserving principles of conceptual clarity and precision.

The Sequence Ontology (SO) is a set of terms and relationships used to describe the features and attributes of biological sequence. The focus of the SO has been the annotation of, or placement of ‘meaning’, onto genomic sequence regions. The VRS effort seeks to use the same descriptive definitions where possible, and to inform the refinement of SO.

The Genotype Ontology (GENO) builds on the SO to include richer modeling of genetic variation at different levels of granularity that are captured in genotype representations. Unlike the SO which is used primarily for annotation of genomic features, GENO was developed by the Monarch Initiative to support semantic data models for integrated representation of genotypes and genetic variants described in human and model organism databases. The core of the GENO model decomposes a genotype specifying sequence variation across an entire genome into smaller components of variation (e.g. allelic composition at a particular locus, haplotypes, gene alleles, and specific sequence alterations). GENO also enables description of biological attributes of these genetic entities (e.g. zygosity, phase, copy number, parental origin, genomic position), and their causal relationships with phenotypes and diseases.

ClinVar is an archive of clinically reported relationships between variation and phenotypes along with interpretations and supporting evidence. Data in ClinVar are submitted primarily by diagnostic labs. ClinVar includes expert reviews and data links to other clinically-relevant resources at NCBI. VRS is expected to facilitate data submissions by providing unified guidelines for data structure and allele normalization.

ClinGen provides a centralized database of genomic and phenotypic data provided by clinicians, researchers, and patients. It standardizes clinical annotation and interpretation of genomic variants and provides evidence-based expert consensus for curated genes and variants. ClinGen has informed the VRS effort and is committed to harmonizing and collaborating on the evolution of the VRS specification to achieve improved data sharing.

HL7 FHIR Genomics, Version 2 Clinical Genomics Implementation Guide, CDA Genetic Test Report: There are several standards developed under the HL7 umbrella that include a genomics component. The FHIR Genomics component was released as part of the overall FHIR specification (latest is Release 3) based on standardized use cases. The HL7 Clinical Genomics (CG) Work Group focuses on developing standards for clinical genomic data and related relevant information within EHRs. The specifications developed by the CG work group primarily utilize the HL7 v2 messaging standard and the newer HL7 FHIR (Fast Healthcare Interoperability Resources) framework.

The SPDI format created to represent alleles in NCBI’s Variation Services has four components: the sequence identifier, which is specified with a sequence accession and version; the 0-based interbase coordinate where the deletion starts; the deleted sequence (or its length) and the inserted sequence. The Variation Services return the minimum deleted sequence required to avoid over precision. For example, a deletion of one G in a run of 4 is specified with deleted and inserted sequences of GGGG and GGG respectively, avoiding the need to left or right shift the minimal representation. This reduces ambiguity, but can lead to long allele descriptions.