Human Genetic Principles: DNA/RNA Structure, Mutation Types, and Nomenclature
Core concepts
Understand the classes of genetic variation: single-nucleotide variants (substitutions), small insertions/deletions, copy-number variants, structural variants, and repeat expansions. Distinguish synonymous, missense, nonsense, frameshift, splice-site, and regulatory variants, and know predicted consequences (loss of function, gain of function, dominant-negative).
Master HGVS nomenclature. Genomic variants use g. (e.g., NM_000546.6:c.215C>G for coding, NC_000017.11:g.7676154A>G for genomic). Coding DNA uses c. with numbering from the A of the ATG start codon; the nucleotide immediately 5' of the start is c.-1, and the 3' UTR begins after the stop codon. Protein changes use p. (e.g., p.Arg175His, or p.R175H in the one-letter form). Insertions, deletions, and duplications are written with ins, del, dup, and delins. Intronic positions use + and - offsets from the nearest exon boundary.
Traps
Examiners love the c. numbering rules (no c.0; the base before A of ATG is c.-1), the three-letter versus one-letter protein conventions, and the difference between a variant of uncertain significance and a pathogenic variant. Also watch for confusion between transcript reference sequences (NM_) and genomic (NC_). A frameshift is not a missense; a splice-site variant may be intronic.
Rule of thumb
Read HGVS left to right as reference:change. Confirm the reference sequence and transcript accession before interpreting the position; the same genomic change may have different c. numbers across transcripts.
Worked example
NM_000546.6:c.818G>A (p.Arg273His) means in transcript NM_000546.6, coding nucleotide 818 changed from G to A, changing arginine at codon 273 to histidine.