A Beginner's Guide to Mutation Nomenclature Using the HGVS Recommendations

Introduction

• Purpose: To simplify the understanding of HGVS nomenclature guidelines, which are globally used for genetic variant interpretation.
• Target Audience: Beginners and professionals involved in clinical diagnostics and genetic research.

What is HGVS Nomenclature?

• Developed by: Human Genome Variation Society (HGVS).
• Purpose: Prevents misinterpretation of DNA, RNA, and protein sequence variants.
• Usage: Widely used in clinical diagnostics and authorized by the Human Genome Organisation (HUGO).
• Terminology Recommendations:
  • Use "Variant" instead of "Mutation" or "Polymorphism".
  • Use "Affects function" instead of "Pathogenic".

Reading Mutation Nomenclature

1. Reference Sequence

• Format: Begins with a reference sequence (e.g., NM-004006.2:c.4375C>T p.(Arg1459*)).
• Accession Number: Two-letter abbreviation followed by a number and version (e.g., NM for protein-coding RNA).
• Abbreviations:
  • NC: Chromosome
  • NG: Gene or genomic region
  • LRG: Locus Reference Genomic sequence
  • NR: Non-protein-coding RNA
  • NP: Protein*

2. Description of Variant

• Notation:
  • ">": Substitution (e.g., c.4375C>T)
  • "del": Deletion (e.g., c.4375_4379del)
  • "dup": Duplication (e.g., c.4375_4385dup)
  • "ins": Insertion (e.g., c.4375_4376insACCT)
  • "delins": Deletion and insertion (e.g., c.4375_4376delinsACTT)

3. Predicted Consequence

• When only DNA is analyzed, predictions at RNA and protein levels are reported in parentheses (e.g., p.(Arg1459*)).*

The 3 Prime Rule

• Description: The nucleotide change is assigned to the most 3' position in the reference sequence.
• Exceptions: Deletions/duplications across exon junctions can be shifted to the next exon.

Final Thoughts and Tools

• Despite initial complexity, understanding HGVS can be simplified with this guide.
• Tool:
  • Alamut Visual Plus: A genome browser that aids in variant interpretation. It uses HGVS recommendations to ensure consistent analysis and reporting.
  • Technical Note: Provides further insights into the application of HGVS guidelines in variant annotation.

Conclusion

• HGVS nomenclature is crucial for accurate genetic variant interpretation.
• This guide helps in breaking down complex nomenclature into understandable segments.

References:

1. Basics of HGVS nomenclature - Link
2. Simple guidelines - Link
3. Standards for nomenclature - Link
4. General recommendations - Link
5. DNAc numbering - Link

Note: Alamut Visual Plus is intended for research use only and not for diagnostic procedures.