PRÁCTICA 4:

NOMENCLATURA DE
VARIANTES GENÉTICAS
Licda. Swuanny Villagran
Genética Laboratorio 2021
NOMENCLATURA • Human Genome Variation Society (HGVS) and
DE LAS American College of Medical Genetics (ACMG)
• http://varnomen.hgvs.org/
VARIANTES
Sample Footer Text 8/23/21 3
 DEFINICIONES EN NOMENCLATURA DE LAS
VARIANTES GENÉTICAS
Table 1. Nomenclature Definitions with Example Variant Descriptions
Substitution (>) g.1318G>T A change where one nucleotide is replaced by one other nucleotide
Deletion| (del) g.3661 3706del A change where one or more nucleotides are not present (deleted)
Inversion (inv) g.495 499inv A change where more than one nucleotide replaces the original sequence and is the
reverse-complement of the original sequence (e.g., CTCGA to TCGAG)
Duplication (dup) g.3661 3706dup A change where a copy of one or more nucleotides are inserted directly 3’ of the original copy of that
sequence
Insertion (ins) g.7339 7340insTAGG A change where one or more nucleotides are inserted in a sequence and where the insertion is not a
copy of a sequence immediately 5’
Conversion (con) g.333 590con1844 2101 A specific type of deletion-insertion where a range of nucleotides replacing the original sequence are a
copy of a sequence from another site in the genome
Deletion-insertion (delins/indel) g.112 117delinsTG A change where one or more nucleotides are replaced by one or more other nucleotides and which is
not a substitution, inversion, or conversion

Read “a change where” as “a change where in a specific sequence compared to the reference sequence . . . ”

period, opened for “Community Consultation.” People interested in Table 2. Reference Sequences
 the reference sequence . . . ”

rested in Table 2.
SECUENCIAS DE
Reference Sequences
REFERENCIA
ensuring
Numbering scheme Prefix Position numbering in relation to
ns made.
d by the Genomic DNAa g. First nucleotide of the genomic reference sequence
oposal is Coding DNAa c. First nucleotide of the translation start codon of the
new ver- coding DNA reference sequence
Noncoding DNAa,b n. First nucleotide of the noncoding DNA reference
osals re-
sequence
rejected. Mitochondrial DNA m. First nucleotide of the mitochondrial DNA
t time in reference sequence
proposals RNA r. First nucleotide of the translation start codon of the
RNA reference sequence or first nucleotide of the
noncoding RNA reference sequence
Protein p. First amino acid of the protein sequence

a
For diagnostic applications, it is strongly recommended to use Locus Reference Ge-
 Coding DNA reference
–3 *3
–93 –2 187 188 *2 *223
–45 –44 –1 1 351 *1 *96 *97

ATG TGA
gtgag..//..tttcag gtaag..//..ttctag gtgag..//..ctttag
–45+1 –44–1 *96+1 *97–1
187+1 188–1
–45+2 –44–2 *96+2 *97–2
187+2 188–2
–45+3 –44–3 *96+3 *97–3
187+3 188–3

Noncoding DNA reference

1 667
49 50 280 281 540 541

gtgag..//..tttcag gtaag..//..ttctag gtgag..//..ctttag

49+1 50–1 280+1 281–1 540+1 541–1
49+2 50–2 280+2 281–2 540+2 541–2
49+3 50–3 280+3 281–3 540+3 541–3

igure 1. Nucleotide numbering for a coding (top) and noncoding (bottom) DNA reference sequence; black box = the protein coding se
n the coding DNA reference sequence, nucleotide numbering starts with c.1 at the A of the ATG translation initiation codon. Numbering p
Impredecible
 49+3 nucleotide50–3 280+3 281–3 540+3 541–3
In the coding DNA reference sequence, numbering starts with c.1 at the A of the ATG translation initiation codon. Numbering proceeds
′
until the last nucleotide of the translation termination codon (TGA, TAA, or TAG). Nucleotides 5 of the ATG are numbered c.-1, c.-2, and so on,
Figure 1. Nucleotide
nucleotides numbering
3′ of the stop for∗ 1,a coding
codon c. (top)
c.∗ 2, and soand
on.noncoding (bottom) DNA
Intronic nucleotides arereference
numbered sequence;
based on black
the box = theflanking
closest protein coding sequence. on the
exon nucleotide,
5In′ side
the coding
goingDNA
into reference
the intronsequence, nucleotide
such as c.187+1, numbering
c.187+2, and sostarts
on,with c.1 at
on the 3′ the
sideA going
of the ATG
in totranslation initiation codon. Numbering proceeds
′the intron such as c.188-1, c.188-2, and so on. When

NUMERACIÓN DEL NUCLEOTIDO

until the last nucleotide of the translation termination codon (TGA, TAA, or TAG). Nucleotides 5 of the ATG are numbered c.-1, c.-2, and so on,
introns have an uneven number of nucleotides, the central nucleotide (N) is linked to the upstream exon, like c.187+N. Nucleotide numbering for a
nucleotides 3′ of the stop codon c.∗ 1, c.∗ 2, and so on. Intronic nucleotides are numbered based on the closest flanking exon nucleotide, on the
noncoding DNA reference sequence starts with nucleotide c. and ends at the end of the reference sequence. Intronic nucleotides are numbered
5′ side going into the intron such as c.187+1, c.187+2, and so on, on the 3′ side going in to the intron such as c.188-1, c.188-2, and so on. When
as for ahave
introns coding DNA reference
an uneven number ofsequence.
nucleotides, the central nucleotide (N) is linked to the upstream exon, like c.187+N. Nucleotide numbering for a
noncoding DNA reference sequence starts with nucleotide c. and ends at the end of the reference sequence. Intronic nucleotides are numbered
as for a3.coding
Table DNA reference
Nucleotide sequence.
Numbering

Table 3. Nucleotide Numbering Genomic reference sequence

Coding DNA reference sequence
Location nucleotide Genomic reference sequence
NC_000023.10 LRG_199 (DMD) LRG_199t1, NM_004006.2
Coding DNA reference sequence
′
5Location
transcription
nucleotidestart g.33231774
NC_000023.10 g.130953
LRG_199 (DMD) c.-2345
LRG_199t1, NM_004006.2
′
In 5 UTR g.33229552 g.133175 c.-123
′ a
5 transcription
(In ′
intron in 5 start UTR) g.33231774 g.130953 c.-2345 (c.-55+23 / c.-54-23)b
AInof5′ the
UTRATG start codon g.33229552
g.33229429 g.133175
g.133298 c.-123 c.1
a
(Incoding
In
′
in 5 UTR)
intron DNA g.32862930 g.499797 (c.-55+23 / c.-54-23)b
c.234
A of
In the ATG
intron, start codon
5′ side g.33229429
g.32380903 g.133298
g.981883 c.1 c.5325+2a
In intron,
In coding DNA3′ side g.32862930
g.32366647 g.499797
g.996080 c.234 c.5326-2a
′ a
GIn of
intron,
TAG 5stopsidecodon g.32380903
g.31140036 g.981883
g.2222791 c.5325+2c.11058
In 3intron,
In ′
′
UTR3 side g.32366647
g.31139691 g.996080
g.2222836 c.5326-2c.a ∗ 345
G of TAG stop codon g.31140036 g.2222791 c.11058 ∗ +
(In intron in 3′ UTR)a (c.. 54 23 / c.∗ 55-23)b
In′ 3′ UTR g.31139691 g.2222836 c.∗ 345 ∗
3 transcription end g.31136580 g.2226247 c. 3456
(In intron in 3′ UTR)a (c..∗ 54+23 / c.∗ 55-23)b
3′ transcription end g.31136580 g.2226247 c.∗ 3456
Nucleotide numbering using a genomic reference sequence (NC_000023.10 [genome build GRCh37/hg19], and LRG_199) and a coding DNA reference sequence (DMD gene,
LRG_199t1, or NM_004006.2). Nucleotide numbering starts at 1; there is no nucleotide 0.
aNucleotide numbering using a genomic reference sequence (NC_000023.10 [genome build GRCh37/hg19], and LRG_199) and a coding DNA reference sequence (DMD gene,
Coding DNA reference sequence NM_004006.2 does not contain intron sequences; LRG_199 is required for this description.
bLRG_199t1, or NM_004006.2). Nucleotide numbering starts at 1; there is no nucleotide
′ ′ 0.
a Hypothetical example, the DMD gene does not contain an intron in the 5 or 3 UTR.
Coding DNA reference sequence NM_004006.2 does not contain intron sequences; LRG_199 is required for this description.
b
Hypothetical example, the DMD gene does not contain an intron in the 5′ or 3′ UTR.
 DESCRIPCIONES A NIVEL DEL ADN
Table 4. DNA Level Descriptions
Variant type g. description c. descriptiona Remarks

Substitution g.32662262G>A c.1318G>A

Deletion g.32466684 32466698del c.3661 3706del Specification of deleted nucleotides(s) optional
Duplication g.32466684 32466698dup c.3661 3706dup Specification duplicated nucleotide(s) optional
Insertion g.31792279 31792280insTAGG c.7339 7340insTAGG Specification of inserted nucleotides mandatory
Inversions g.32481638 32481654inv c.3334 3350inv Minimum size: 2 nucleotides
Deletion-insertion (indel) g.32867914 32867919delinsTG c.112 117delinsTG Specification of inserted nucleotides mandatory
Translocation No recommendation yetb
Repetitive DNA stretch g.31836932T[22] c.7309+1160T[22] Describe first nucleotide and repeat unit or range
g.33170306TAA[9] or c.31+59093TAA[9] or of first repeat unit with number of repeat units
g.33170306 33170308[9] c.31+59093 31+59095[9] between brackets
Two variants on one chromosome g.[32841486C>T;33038273G>C] c.[76C>T; 283G>C]
(in cis)
Two variants on two different c.[76C>T];[283G>C]
chromosomes (in trans) g.[32841486C>T];[33038273G>C]
Two variants, phase unknown (on c.[76C>T(;)283G>C]
one or two chromosomes) g.[32841486C>T(;)33038273G>C]

Variants are described in relation to hypothetical genomic and coding DNA reference sequences. A more extensive collection of examples is available from the HGVS nomenclature
Website.
a
For another location of the nucleotide relative to a coding DNA reference sequence, see Table 3.
b
Subject of proposal SVD-WG004.

Table 5. RNA Level Descriptions “+” character was used both in nucleotide numbering (for intronic
 Table 5. RNA Level Descriptions “+” cha
nucleo
Variant type r. description Remarks
menda
Substitution r.1318g>u “;” to l
Deletion r.3661 3706del No specification of variant
deleted nucleotide(s) for the
Duplication r.3661 3706dup No specification of
trans),
duplicated
nucleotide(s) unknow
Insertion r.7339 7340instagg Mandatory “+” to
r.456 457ins456+87 456+121 specification of at DNA
inserted (2000)
nucleotide(s)
Inversions r.3334 3350inv Minimum size 2
ble 5).
nucleotides The

DESCRIPCIONES A
Deletion-insertion r.112 117delinsug Mandatory nucleo
(indel) specification of
direct a
inserted nucleotides

NIVEL DEL ARN Two variants on

1 chromosome (in cis)
r.[76c>u;283g>c] scheme
ment o
Two variants on differentr.[76c>u];[283g>c] Checke
chromosomes ommen
(in trans)
Two variants, phase r.[76c>u(;)283g>c]
should
unknown Reco
One DNA change r.[76a>c,70 77del] have n
yielding two plicatio
transcripts
descrip
Predictions r.spl r.? Affects splicing
unknown format
consequences tions a
was th
Variants are described in relation to a hypothetical RNA reference sequence. Compared
with DNA descriptions, lower case nucleotides are used and “u” instead of “t.” A more
fore ha
extensive collection of examples is available from the HGVS nomenclature Website. g.(1234
sequen
 Table 6. Protein Level Descriptions
Variant type p. description Remarks
p.(Arg490Ser) The protein change is
predicted (no
experimental proof)
Substitution p.Arg490Ser/p.R490S Both three- (preferred)
p.Trp87Ter / and one-letter amino
p.Trp78∗/p.W87∗ acid code may be used;
∗ accepted for one-
and three-letter code
Deletion p.Asp388 Gln393del No specification of
deleted amino acid(s)
Duplication p.Asp388 Gln393dup No specification of
duplicated amino
acid(s)
Insertion p.Ala228 Val229insTrpPro Mandatory specification
the protein level should make
was available or not. When not
sequences in parentheses. Vari
translational reading frame sho
or a long form; p.(Arg97fs) an
For “fsTer#”/”fs∗#,” it is specifie
number the new reading frame e
of the stop in the new reading fr
amino acid that is changed by
codon (∗#).
A newly added recommenda
affecting the start or stop codon
Amino acids upstream of the or
a minus sign. For example, p.M

DESCRIPCIONES A NIVEL
p.Ala228 Val229insLys∗ of inserted amino acids served N-terminal extension of
Inversions Not possible
of the protein as the consequen
Deletion-insertion p.L7 H8delinsWQQFRTG Mandatory specification

DE PROTEÍNAS
(indel) of inserted amino acids changes amino acid Met1 to Val
Frame shift p.(Arg97fs) Short and long form scribes the observed extension o
p.(Arg97Profs∗23) accepted; long form 17 new amino acids as a conseq
contains “fsTer” or that changes Ter110 to Gln.
“fs∗”
Extension p.Met1ValextMet-12 Short and long form
p.Ter110GlnextTer17 accepted; long form
contains “fsTer” or Community Consultation
“fs∗”
Repetitive amino acid p.Gln34[22] p.Ser7 Ala9[6] Describe first amino acid The Sequence Variant Descr
stretch repeat unit currently commissioning the va
Two protein coding p.[Trp78∗;Arg490Ser] under the auspices of HGVS, H
variants on one
the first round of proposals. P
chromosome (in cis)
Two protein coding p.[Trp78∗];[Arg490Ser] allowing the description g.123G
variants on two was performed but no change
different chromosomes g.456G>A has no predicted con
(in trans) can be described as p.(Arg152
Two protein coding p.[Trp78∗(;)Arg490Ser]
variants, phase
cepted allowing the use of a n
unknown using the prefix “n.” (n.963G>
Predictions p.? Unknown consequences to further specify the descript
detected using MLPA is still un
Variants are described in relation to a hypothetical protein reference sequence. A more
extensive collection of examples is available from the HGVS nomenclature Website.
going to achieve a harmonizati
the HGVS and the Internation
Cytogenetic Nomenclature [IS
Ejemplos de Nomenclatura
• c.76A>C denotes that at nucleotide 76 an A is changed to a C
• c.-14G>C denotes a G to C substitution 14 nucleotides 5' of the ATG translation
initiation codon
• c.88+1G>T denotes the G to T substitution at nucleotide +1 of an intron (in the
coding DNA positioned between nucleotides 88 and 89)
• c.89-2A>C denotes the A to C substitution at nucleotide -2 of an intron (in the
coding DNA positioned between nucleotides 88 and 89)
• c.*46T>A denotes a T to A substitution 46 nucleotides 3' of the translation
termination codon
• ACTTTGTGCC to ACTTGCC is described as c.5_7del (c.5_7delTGT, not as c.4_6delTTG)
Ejercicios Nomenclatura
1. c.76A>C 10. r.3334 _3350inv
2. c.-14G>C 11. r.112 _117delinsug
3. c.88+1G>T 12. g.21538G >A (c.*97G>A)
4. c.89-2A>C 13. c.1601G >A (p.Arg534>Gln)
5. c.*46T>A 14. c.665C >T (p.Ala222Val)
6. p.Gly85Glu 15. c.845G>A (p.Cys282Tyr)
7. p.Arg117His
8. p.Ile507del
9. p.Phe508del