Variant Effects
A variant is a change in the DNA sequence. Whether it matters depends on where it falls and what it does to the protein that the DNA codes for. The mutation tool takes a coding sequence and a list of changes and works out the consequence of each.
Writing a change: HGVS
The standard notation is HGVS. c.35G>A means that in the coding DNA, counting from the A of the ATG start codon as base 1, base 35 is a G that becomes an A. Other forms are c.35del (deletion), c.35_36insGG (insertion between 35 and 36), c.35dup (duplication) and c.35_37delinsAA (replacement). The protein-level result uses p.: KRAS c.35G>A turns GGT (glycine) into GAT (aspartate), written p.Gly12Asp, a well-known cancer mutation. For repeats, HGVS asks for the most 3' position of an insertion or deletion to be named.
How different is the new amino acid?
Two scores help rate a missense change. Grantham distance (0 to 215) measures the chemical difference between two amino acids from composition, polarity and volume: the larger, the more drastic the swap. A common grouping (Li et al. 1984) calls 0–50 conservative, 51–100 moderately conservative, 101–150 moderately radical and above 150 radical. BLOSUM62 counts how often evolution accepts the swap: positive is common, negative is rare.
How Aaron's Archive does it
| Item | What the tool does |
|---|---|
| Input | A coding DNA sequence beginning at the ATG and a list of changes in c. notation, one per entry. If the base you name does not match your sequence, the tool says what is really there. |
| Output | The codon change, the protein change in p. notation, the consequence class and, for missense changes, the Grantham distance with its class and the BLOSUM62 score. Frameshifts report the first changed amino acid and, when the shifted frame reaches one, where the new protein ends. |
| Check | Grantham values agree with the published matrix to within 1 for 189 of 190 amino-acid pairs. |
| Limit | Up to 1,000,000 bp. |
What it cannot tell you
These are predictions from sequence alone. A drastic-looking swap can be harmless and a conservative one can break a critical site. The tool does not know about splicing, the structure of the protein, where it works in the cell, or what is already known about the variant. For clinical or research conclusions use curated resources such as ClinVar and gnomAD, and expert interpretation.
Common questions about variant effects
What do silent, missense and nonsense mean?
A silent change leaves the amino acid the same. A missense change swaps it for a different one. A nonsense change turns a codon into a stop, which usually shortens the protein.
What is a frameshift?
Deleting or inserting bases that are not a multiple of three shifts the reading frame, so every codon after the change is read differently, usually ending at an early stop.
What do c. and p. mean in HGVS notation?
c. numbers the coding DNA from the A of the start codon; p. names the change in the protein. For example c.35G>A gives p.Gly12Asp in KRAS.
Does a high Grantham score mean a variant is harmful?
No. It only measures how different two amino acids are. Whether a change causes disease depends on where it falls and on evidence beyond this tool.
Where can I check a change?
Use the mutation effect predictor.