G- HGVS nomenclature

HGVS nomenclature

Genomic vs coding nomenclature

cons of genomic

• in humans, genomic seq does not have any useful info but coding does

• very long genes → nuv number very high

• genes can have introns with lenght variants present in population, so one ref seq is not possible

pros of coding

• nomenclature gives some info about location of the variant (exon,intron,UTR)

cons of coding

• exact location of start codon is not always known (cannot assign nuc 1)

• gene may have several transcrips and a complete ref seq cannot be determined

con for both

• if different genes overlap, what reference should be used

general recommendations ofr codin seq

genomic ref used should be given in the nomenclature

coding seq should come from the RefSeq database (listing both the database accession and version number)

labs should come to a consensus and use one coding DNA ref seq

use official HGNC gene symbols to describe gene (BRCA1, HFE…)

description should be preceded by a letter for the type of ref seq used (c. = coding, g. = genomic, p. = protein)

nuc numbering c.

there is no nuc 0

nuc 1 = the A of the ATG-translation initiation codon (AUG)

• exception for some genes (HBB gene)

the nuc immediatly 5’ of 1 is -1 (5’UTR region)

the nuc immediatly after the stop codon is *1 (3’ UTR region)

introns

• first half of the intron takes the last nuc of the exon before the intron and +# of nuc away

• second half takes the first nuc of the next exon and -#

• if odd number of nucs in the intron, the middle nuc is described with a +

3’ rule

• when in doubt the most 3’ nuc position possible is arbitrarily assigned to have been changed

• important when single nuc is repeated or for tandem repeats

symbols in c.

an allele is identified by surrounding it with [var]

if both alleles have variants seperated by ; → c.[var];[var]

if 2 variants on same allele → c.[var;var]

when 2 variants but unknown alleles → c.var(;)var

• never acceptable to report in clinical

substitution = >

• c.79A>T (A was changed to a T)

insertion = ins

• c.79_80insT (T was added between nuc 79 and 80)

duplication = dup

• should use dup over ins when applicable

• c.79dup (dont need base)

deletion = del

• c.79del (dont need base)

replacement = delins

inversion = inv

if theres a range of affected bases = _ → #_#

the equal symbol → seq was tested but found unchanged

• c.[79A>T];[79=]

• we always report both alleles

p. symbols

still use same rules for [ ] and ;

• do not need to include equal to show the other allele when reporting

• dont need brackets unless both alleles are patho

use ( ) when predicted consequences (goes inside [ ] when needed)

ins, dup, del, delins mean the same thing

• p.AA#AA = sub

• p.AA#del or dup

• p.AA#_AA#delinsAAAAAA

_ and = mean the same

to indicate a stop codon = Ter or *

• p.AA#Ter or p.AA#*

fs = frame shift

• caused by ins or del of nucs (not x3)

• often leads to an early sstop codon →truncated protein

• short form = p.AA#fs

• long form = p.AA#AAfsTer$</p><ul><li><p>$ refers to the position in the new reading frame where the stop codon is (count from the first AA change)

• use the AA# where the first change happens (not where the nuc changes first)

• we always use long form

? indicates an unknown change (often used for splicing variants)

3’ rule applies