NM_004006.3:c.8255A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_004006.3(DMD):​c.8255A>G​(p.Tyr2752Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000247 in 1,208,631 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 93 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y2752H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., 5 hem., cov: 23)
Exomes 𝑓: 0.00026 ( 0 hom. 88 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

1
6
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:5

Conservation

PhyloP100: 3.34

Publications

0 publications found
Variant links:
Genes affected
DMD (HGNC:2928): (dystrophin) This gene spans a genomic range of greater than 2 Mb and encodes a large protein containing an N-terminal actin-binding domain and multiple spectrin repeats. The encoded protein forms a component of the dystrophin-glycoprotein complex (DGC), which bridges the inner cytoskeleton and the extracellular matrix. Deletions, duplications, and point mutations at this gene locus may cause Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), or cardiomyopathy. Alternative promoter usage and alternative splicing result in numerous distinct transcript variants and protein isoforms for this gene. [provided by RefSeq, Dec 2016]
DMD Gene-Disease associations (from GenCC):
  • Becker muscular dystrophy
    Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
  • dilated cardiomyopathy 3B
    Inheritance: XL Classification: DEFINITIVE Submitted by: Ambry Genetics
  • Duchenne and Becker muscular dystrophy
    Inheritance: XL Classification: DEFINITIVE Submitted by: Myriad Women’s Health
  • Duchenne muscular dystrophy
    Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
  • progressive muscular dystrophy
    Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
  • familial isolated dilated cardiomyopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • non-syndromic X-linked intellectual disability
    Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
  • symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers
    Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.23642498).
BP6
Variant X-31507416-T-C is Benign according to our data. Variant chrX-31507416-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94797.
BS2
High AC in GnomAd4 at 17 XL,AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DMDNM_004006.3 linkc.8255A>G p.Tyr2752Cys missense_variant Exon 56 of 79 ENST00000357033.9 NP_003997.2 P11532

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DMDENST00000357033.9 linkc.8255A>G p.Tyr2752Cys missense_variant Exon 56 of 79 1 NM_004006.3 ENSP00000354923.3 A0A075B6G3

Frequencies

GnomAD3 genomes
AF:
0.000151
AC:
17
AN:
112350
Hom.:
0
Cov.:
23
show subpopulations
Gnomad AFR
AF:
0.0000647
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000945
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000263
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000168
AC:
30
AN:
178045
AF XY:
0.0000794
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000369
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000369
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000256
AC:
281
AN:
1096281
Hom.:
0
Cov.:
30
AF XY:
0.000243
AC XY:
88
AN XY:
361749
show subpopulations
African (AFR)
AF:
0.0000379
AC:
1
AN:
26382
American (AMR)
AF:
0.0000285
AC:
1
AN:
35078
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19353
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30175
South Asian (SAS)
AF:
0.00
AC:
0
AN:
53829
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40390
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4135
European-Non Finnish (NFE)
AF:
0.000318
AC:
267
AN:
840919
Other (OTH)
AF:
0.000261
AC:
12
AN:
46020
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.474
Heterozygous variant carriers
0
10
20
31
41
51
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
20
40
60
80
100
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000151
AC:
17
AN:
112350
Hom.:
0
Cov.:
23
AF XY:
0.000145
AC XY:
5
AN XY:
34500
show subpopulations
African (AFR)
AF:
0.0000647
AC:
2
AN:
30928
American (AMR)
AF:
0.0000945
AC:
1
AN:
10580
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
2652
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3595
South Asian (SAS)
AF:
0.00
AC:
0
AN:
2740
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
6104
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
240
European-Non Finnish (NFE)
AF:
0.000263
AC:
14
AN:
53316
Other (OTH)
AF:
0.00
AC:
0
AN:
1511
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000172
Hom.:
3
Bravo
AF:
0.000178
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000149
AC:
1
ExAC
AF:
0.000181
AC:
22

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:1
Mar 02, 2021
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Aug 10, 2016
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 20, 2021
Revvity Omics, Revvity
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Uncertain:1Benign:1
Feb 16, 2025
Laboratory of Genetics, Children's Clinical University Hospital Latvia
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Sep 26, 2018
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The DMD p.Tyr2752Cys variant (rs373832446), to our knowledge, has not been reported in the medical literature or gene specific databases; however, this variant is also listed in the ClinVar database with conflicting interpretations (Variation ID: 94797). This variant is found in the general population with an allele frequency in non-Finnish Europeans of 0.03% (28/87,438 alleles; including 5 hemizygotes) in the Genome Aggregation Database. The tyrosine at codon 2752 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Thus, based on the available information, the clinical significance of this variant is uncertain. -

DMD-related disorder Benign:1
Jun 12, 2024
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1
Jan 12, 2022
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Duchenne muscular dystrophy Benign:1
Dec 09, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.29
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.22
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.39
.;T;T;T;.;.;T;.;.;T
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.97
D;.;.;.;.;D;.;D;D;.
M_CAP
Benign
0.058
D
MetaRNN
Benign
0.24
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.86
T
PhyloP100
3.3
PrimateAI
Uncertain
0.67
T
PROVEAN
Pathogenic
-4.5
D;.;D;D;D;.;D;.;D;D
REVEL
Benign
0.27
Sift
Uncertain
0.0040
D;.;D;D;D;.;D;.;D;D
Sift4G
Uncertain
0.019
D;D;D;D;D;D;D;D;D;D
Polyphen
0.99, 1.0, 0.98, 0.97
.;.;D;D;D;.;D;.;.;D
Vest4
0.77, 0.78, 0.77, 0.79, 0.67, 0.71, 0.77, 0.78
MVP
0.64
MPC
0.10
ClinPred
0.42
T
GERP RS
4.3
gMVP
0.61
Mutation Taster
=99/1
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs373832446; hg19: chrX-31525533; API