Variant nomenclature

Given the number of different types of variants, researchers and clinicians must describe them in a standardised manner to avoid any confusion. The Human Genome Variation Society (HGVS) defined a ‘common language’ or standard nomenclature to describe variations found in DNA, RNA and protein sequences, as follows:

reference sequence : variant description

Reference sequence: also referred to as RefSeq, is the GenBank accession number, which is a standardised representation of the human genome used by researchers when comparing with other genomes.

Variant description: indicates the type of reference used, the location in the coding sequence where the change occurs, and the residue (nucleotide or amino acid) change.

Let’s break down this example:

NM_004006.2 : c. 4375C>T p. (Arg1459*)

NM_ = RefSeq GenBank code to indicate the reference is based on a coding transcript code (mRNA)
004006.2 = GenBank accession number for the sequence
c. = indicates that the position refers to the coding DNA sequence
4375 = the residue position
C>T = nucleotide change from cytosine (C) to thymine (T)
p. = indicates that the predicted effect is at the protein level
(Arg1459*) = the amino acid arginine (Arg) at position 1459 is changed to a stop codon ( * ). This change is likely to result in a truncated, non-functional protein.

Although variants are usually reported based on the coding DNA reference sequences (c.), they can also be described based on a genomic reference sequence (g.) or a non-coding DNA sequence (n.), for example. A comprehensive list of coding nomenclature can be found at the HGVS nomenclature website. We recommend that you bookmark this website and return to it for consultation throughout the course. In the additional files below, you can download a table with more examples of how to use the standard nomenclature to describe genetic variants.

Understanding how to apply appropriate nomenclature is pivotal when using variant interpretation tools such as the Matched Annotation from NCBI and EBI (MANE) or the most clinically relevant transcripts, aiming to cover a high-confidence, genome-wide transcript set. You will learn more about MANE in Week 2.

On the other hand, tools like the Mutalyzer and VariantValidator are designed to check whether your variant description is accurate and uses the correct format.

Ready for a deeper dive into variant nomenclature? Input the sickle cell disease variant NM_000518.5:c.20A>T in VariantValidator. After running the check, share your results and reflections in the comments section. How many ways can this same variant be described? Why do you think that happens? Discuss your thoughts with your fellow learners.