chrX-31627731-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004006.3(DMD):​c.8159G>A​(p.Arg2720His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000182 in 1,209,456 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2720P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)
Exomes 𝑓: 0.000018 ( 0 hom. 6 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

16

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:3

Conservation

PhyloP100: 1.06

Publications

1 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 -16 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.06558317).
BP6
Variant X-31627731-C-T is Benign according to our data. Variant chrX-31627731-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 409916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAdExome4 at 20 XL,AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DMDNM_004006.3 linkc.8159G>A p.Arg2720His missense_variant Exon 55 of 79 ENST00000357033.9 NP_003997.2 P11532

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DMDENST00000357033.9 linkc.8159G>A p.Arg2720His missense_variant Exon 55 of 79 1 NM_004006.3 ENSP00000354923.3 A0A075B6G3

Frequencies

GnomAD3 genomes
AF:
0.0000179
AC:
2
AN:
111638
Hom.:
0
Cov.:
23
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000376
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000329
AC:
6
AN:
182409
AF XY:
0.0000447
show subpopulations
Gnomad AFR exome
AF:
0.0000762
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000369
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000182
AC:
20
AN:
1097818
Hom.:
0
Cov.:
31
AF XY:
0.0000165
AC XY:
6
AN XY:
363234
show subpopulations
African (AFR)
AF:
0.000114
AC:
3
AN:
26392
American (AMR)
AF:
0.0000284
AC:
1
AN:
35193
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19380
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30178
South Asian (SAS)
AF:
0.0000185
AC:
1
AN:
54095
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40497
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4107
European-Non Finnish (NFE)
AF:
0.0000178
AC:
15
AN:
841902
Other (OTH)
AF:
0.00
AC:
0
AN:
46074
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.486
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome 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
GnomAD4 genome
AF:
0.0000179
AC:
2
AN:
111638
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
33832
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
30731
American (AMR)
AF:
0.00
AC:
0
AN:
10400
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
2639
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3558
South Asian (SAS)
AF:
0.00
AC:
0
AN:
2685
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
5988
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
239
European-Non Finnish (NFE)
AF:
0.0000376
AC:
2
AN:
53215
Other (OTH)
AF:
0.00
AC:
0
AN:
1497
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.550
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
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:
0.00
Hom.:
0
Bravo
AF:
0.0000529
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000596

ClinVar

Significance: Likely benign
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency Uncertain:1
Apr 20, 2020
Natera, Inc.
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

not specified Benign:1
Jan 23, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: DMD c.8159G>A (p.Arg2720His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 1209456 control chromosomes, including 6 hemizygotes. The observed variant frequency is approximately 1.65 fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophinopathies phenotype (1.1e-05). To our knowledge, no occurrence of c.8159G>A in individuals affected with Dystrophinopathies and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 409916). Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiovascular phenotype Benign:1
Sep 04, 2019
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
Nov 24, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.064
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.68
CADD
Benign
12
DANN
Benign
0.44
DEOGEN2
Benign
0.24
.;T;T;.;.;T;.;.;T
FATHMM_MKL
Benign
0.31
N
LIST_S2
Benign
0.61
T;.;.;.;T;.;T;T;.
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.066
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
PhyloP100
1.1
PrimateAI
Benign
0.24
T
PROVEAN
Benign
0.71
N;N;N;N;.;N;.;N;N
REVEL
Benign
0.062
Sift
Benign
0.63
T;T;T;T;.;T;.;T;T
Sift4G
Benign
0.36
T;T;T;T;T;T;T;T;T
Polyphen
0.0
.;B;B;B;.;B;.;.;B
Vest4
0.072, 0.076, 0.059, 0.098, 0.070, 0.087, 0.079
MutPred
0.45
.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0804);.;
MVP
0.41
MPC
0.016
ClinPred
0.047
T
GERP RS
1.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
gMVP
0.096
Mutation Taster
=100/0
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: rs760495223; hg19: chrX-31645848; COSMIC: COSV105915764; API