HGVS Nomenclature

The Human Genome Variation Society (HGVS) nomenclature is the standard system for describing sequence variants at the DNA, RNA, and protein levels. It uses specific prefixes and conventions to ensure unambiguous communication of molecular findings in clinical reports, publications, and genomic databases.

Reference Sequence Prefixes

• c.: coding DNA sequence (numbered relative to the ATG start codon, where A of ATG = nucleotide 1). Uses an NM_ transcript reference.
• g.: genomic DNA sequence (numbered relative to a chromosomal or genomic reference, e.g., NC_ accession). Used for variants described at the genome level.
• p.: protein sequence (numbered from the initiator methionine = residue 1). Uses an NP_ protein reference. Three-letter amino acid codes are standard in clinical reports; single-letter codes are acceptable in research.
• r.: RNA sequence (rarely used clinically but describes changes at the transcript level).
• m.: mitochondrial DNA sequence.

Reference Sequence Identifiers

• NM_: NCBI RefSeq mRNA transcript (e.g., NM_000492.4 for CFTR). The number after the period is the version.
• NP_: NCBI RefSeq protein (e.g., NP_000483.3 for CFTR protein)
• NC_: NCBI RefSeq genomic chromosome
• LRG_: Locus Reference Genomic sequences (stable, non-versioned references)

Common Variant Types with Examples

• Missense (amino acid substitution):

  • DNA: c.1624G>T (guanine to thymine at position 1624)
  • Protein: p.(Val542Phe) or p.(V542F): parentheses indicate the protein change is predicted, not experimentally confirmed

• Nonsense (premature stop codon):

  • DNA: c.1657C>T
  • Protein: p.(Arg553Ter) or p.(R553*): "Ter" or "*" indicates a stop codon

• Frameshift:

  • DNA: c.1521_1523delCTT (deletion of 3 nucleotides; but if not a multiple of 3 at the protein level, it causes a frameshift)
  • DNA: c.1585_1586insT (insertion of a T between positions 1585 and 1586)
  • Protein: p.(Leu512ProfsTer28): the new reading frame encounters a stop codon 28 residues after the first altered amino acid. "fs" = frameshift.

• Splice site:

  • c.1585-1G>A: variant at the -1 position of intron (one nucleotide before the exon start, affecting the acceptor splice site)
  • c.1584+1G>T: variant at the +1 position of intron (one nucleotide after the exon end, affecting the donor splice site)
  • Intronic positions use + (downstream of exon, donor end) or - (upstream of exon, acceptor end) relative to the nearest exon boundary

• In-frame deletion:

  • DNA: c.1521_1523delCTT (deletion of exactly 3 nucleotides)
  • Protein: p.(Phe508del): the classic CFTR delta-F508 variant. An in-frame deletion removes one or more amino acids without altering the reading frame.

• Synonymous (silent):

  • DNA: c.1503C>T
  • Protein: p.(Ala501=): the "=" indicates no amino acid change. Note: synonymous variants can still affect splicing.

• Duplication:

  • DNA: c.1519_1521dupATT: duplication of 3 nucleotides
  • Preferred over describing as an insertion when the added sequence is identical to the adjacent sequence

Numbering Conventions

• Coding sequence: Position 1 = the A of the ATG initiation codon. The nucleotide immediately before it is -1 (in the 5' UTR). There is no position 0.
• Intronic positions: Described relative to the nearest exon boundary. E.g., c.1585+5G>A is 5 nucleotides into the intron downstream of coding position 1585.
• 3' UTR: Positions downstream of the stop codon use * prefix. E.g., c.*10A>G is 10 nucleotides after the stop codon.

• Standardized reporting: All clinical molecular genetic reports should use HGVS nomenclature. Ensures unambiguous communication between laboratories, clinicians, and databases.
• Database queries: Searching ClinVar, HGMD, and gene-specific databases requires accurate HGVS descriptions. Incorrect nomenclature may lead to missed results.
• Genetic counseling: Genetic counselors must be able to read and explain HGVS-formatted variants to patients and referring providers.
• Legacy nomenclature: Older publications and some clinical contexts still use legacy names (e.g., "delta-F508" instead of p.(Phe508del)). Be prepared to recognize and translate these.

• Transcript-dependent: The same genomic variant can have different c. and p. descriptions depending on which transcript is used. Always check the reference sequence (NM_ number and version).
• Does not indicate pathogenicity: HGVS nomenclature describes the change but does not convey whether it is pathogenic, benign, or of uncertain significance.
• Protein predictions may be inaccurate: The p. description is predicted from the DNA change. Actual protein effects may differ due to alternative splicing, nonsense-mediated decay, or other post-transcriptional mechanisms. Parentheses around the protein change indicate it is predicted.
• Complex variants: Some complex rearrangements, compound variants, or phased variants can be difficult to represent accurately.