Table 1 Comparison of sequence variant representation and presentation standards. Coordinate systems describes the distinct ways in which position may be defined on a reference sequence. Normalization describes the convention by which deletion/insertion variants are normalized (also referred to as aligned, shuffled, or shifted) in the context of sequence repeats. Variant primitive operations describes the distinct primitive operations that are supported by the standard; “deletion/insertion” in this column refers to the replacement of a span of sequence with another sequence, either of which might be zero-length. Primary uses, strengths, and limitations provides a cursory and incomplete summary of typical usage; nuances are omitted for brevity. The phrase “deletion/insertion” is used to describe deletion, insertion, and combined deletion and insertion variant types

Human Genome Variation Society (HGVS) Nomenclature

Human Genome Organization (HUGO)

• DNA

• RNA

• Protein

• Contiguous linear from sequence start or transcription start

• Discontiguous exonic/intronic

• Circular

• Right-justified normalization

• Substitution

• Deletion/insertion

• Adjoined transcripts

• Duplication

• Extension

• Frameshift

• Inversion

• Repeat

Predominant standard in representing variation in databases, publications, and clinical reports. Supports most sequence and variant types. as well as phased alleles and HGVS/ISCN Optionality desired by user groups necessarily creates some ambiguity

International System for Cytogenomic Nomenclature (ISCN)

• DNA

• Chromosomal bands

• Contiguous linear normalization

• Aneuploidy

• Derived chromosomes

• Amplification

• Deletion

• Insertion

• Duplications

• Gene fusions

• Inversions

• Translocations

• ISCN/HGVS

Long-standing standard for reporting genomic variation from karyotypes, FISH, microarray, genome mapping, and region-specific assays in constitutional and neoplasia cytogenomics. Represents variants not easily represented by other standards

Sequence Position Deletion Insertion (SPDI)

National Center for Biotechnology Information (NCBI)

• DNA

• RNA

• Protein

• Contiguous linear

• Fully justified normalization

• Deletion/insertion (as a generalization of substitutions, duplications, inversions, etc.)

Primarily used within NCBI for the precise and unambiguous representation of variants that can be represented as a combination of deletion and insertion events. The fully justified normalization using the SPDI algorithm expresses position ambiguity of variants in repeat regions better than left- or right-justified/normalized/shuffled variants

Variant Call Format (VCF)

Global Alliance for Genomics and Health (GA4GH)

• DNA

• Contiguous linear

• Left-justified normalization, with anchor

• Deletion/insertion

• Deletion (DEL)

• Breakend (BND)

• Copy number (CNV)

• Insertion (INS)

• Inversion (INV)

• Translocation (TRA)

The de facto standard file format for storing variants from NGS. Provides support for annotations, quality scores, and multiple samples within a single file. Supports only genomic sequences and file-based storage

Variation Representation Specification (VRS)

Global Alliance for Genomics and Health (GA4GH)

• DNA

• RNA

• Protein

• Contiguous linear

• Fully justified normalization

• Deletion/insertion

• Adjoined sequences

• Copy number

• Genotype

• Haplotype

• Repeat

Extensible standard for representing variants on all sequence types and sharing variants between systems and in complex data structures. Primarily focused on precise representation and the minimization of ambiguity, but also supports affirmative imprecision of some concepts. Semi-structured representation limits human readability