a sequence change extending the reference amino acid sequence at the N- or C-terminal end with one or more amino acids.
Format (N-terminal): “prefix”“Met1”“ext”“position_new_initiation_site”, e.g. p.Met1ext-5
“prefix” = reference sequence used = p. “Met1” = normal translation initiation site = Met1 “ext” = type of change is an extension = ext “position_new_initiation_site” = position new upstream translation initiation site = -5
Format (C-terminal): “prefix”“Ter_position”“new_amino_acid”“ext”“Ter”“position_new_termination_site”, e.g. p.Ter110Glnext\Ter17
“prefix” = reference sequence used = p. “Ter_position” = normal translation termination site = Ter110 “new_amino_acid” = amino acid encoded by variant termination codon = Gln “ext” = type of change is an extension = ext “Ter” = termination codon = Ter / * “position_new_termination_site” = position new downstream translation termination site = 17
all variants should be described at the DNA level, descriptions at the RNA and/or protein level may be given in addition
prefix reference sequence accepted is “p.” (protein).
extension variants have been accepted on 2012-08-31.
predicted consequences, i.e. without experimental evidence (no RNA or protein sequence analysed), should be given in parentheses, e.g. p.(Ter110GlnextTer17) or p.(*110Glnext*17).
variants affecting the translation initiation site (Met1) activating an upstream (N-terminal) translation initiation site are described as deletion-insertion, those activating a downstream (C-terminal) initiation site as a deletion.
prioritisation: (1) extension, (2) frame shift or deletion-insertion.
a variant in the 5’ UTR activates a new upstream translation initiation site starting with amino acid Met-5
NOTE: modified from p.Met1extMet-5
amino acid Met1 is changed to Val activating an upstream translation initiation site at position -4 (Met-4), insertion amino acids ArgSerThrVal between Mat1 and Leu2.
NOTE: this variant is not described as an extension (p.Met1Valext-4) since Met1, part of the normal amino acid sequence, is changed
a variant in the stop codon (Ter/*) at position 110, changing it to a Gln-codon (a no-stop variant) and adding a tail of new amino acids to the protein’s C-terminus, ending at a new stop codon (Ter/*) at position 17
p.Ter327Argext*? (alternatively p.*327Argext*?)
a variant in the stop codon (Ter/*) at position 327, changing it to an Arg-codon and adding a tail of new amino acids of unknown length (position *?) since the shifted frame does not contain a new stop codon.
How are variants at the protein level called that directly affect the translation initiation (start) codon?
The variant is called start-lost variant, one of two types of a protein extension, an N-terminal extension. Note the difference with a start-gained variant where the start codon itself is not directly affected, another type of N-terminal extension.
How are variants at the protein level called that directly affect the translation termination (stop) codon?
The variant is called a no-stop or stop-lost variant, one of two types of a protein extension, a C-terminal extension.
How do I describe an extension when no new stop codon is reached?
Such variants are described using the format p.Ter789ArgextTer?, i.e. "extTer?" to indicate that no new termination codon is encountered.
How should a variant in the 5'UTR be described that gives rise to a new translation initiation site?
Description at the DNA-level is like c.-23A>T (changing c.-25 caGggt c.-19 to caTggt, creating a new ATG-triplet). Description at the RNA-level is r.-23a>u and at the protein level p.(Met1ext-8), indicating the predicted protein sequence is an N-terminal extension with 8 amino acids.
Should I describe a duplication in the translation termination codon (TGA to TGGA) as a frame shift or as an extension?
The variant extends the amino acid sequence at the C-terminal end and is therefore by definition an extension.