X-31478309-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004006.3(DMD):c.8734A>G(p.Asn2912Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,209,467 control chromosomes in the GnomAD database, including 198 homozygotes. There are 5,390 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 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. N2912S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.029 ( 85 hom., 880 hem., cov: 23)

Exomes 𝑓: 0.013 ( 113 hom. 4510 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:17

Conservation

PhyloP100: 0.521

Publications

15 publications found

Variant links:

COSMIC-nc: COSV104414665

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

DMD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015425086).

BP6

Variant X-31478309-T-C is Benign according to our data. Variant chrX-31478309-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 11268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.8734A>G	p.Asn2912Asp	missense_variant	Exon 59 of 79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9 link	c.8734A>G	p.Asn2912Asp	missense_variant	Exon 59 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes

AF:

0.0286

AC:

3178

AN:

111262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0172

Gnomad ASJ

AF:

0.0185

Gnomad EAS

AF:

0.0434

Gnomad SAS

AF:

0.00842

Gnomad FIN

AF:

0.0149

Gnomad MID

AF:

0.0210

Gnomad NFE

AF:

0.00956

Gnomad OTH

AF:

0.0234

GnomAD2 exomes

AF:

0.0213

AC:

3896

AN:

183245

AF XY:

0.0179

show subpopulations

Gnomad AFR exome

AF:

0.0767

Gnomad AMR exome

AF:

0.0246

Gnomad ASJ exome

AF:

0.0168

Gnomad EAS exome

AF:

0.0458

Gnomad FIN exome

AF:

0.0194

Gnomad NFE exome

AF:

0.0102

Gnomad OTH exome

AF:

0.0157

GnomAD4 exome

AF:

0.0133

AC:

14646

AN:

1098149

Hom.:

113

Cov.:

AF XY:

0.0124

AC XY:

4510

AN XY:

363505

show subpopulations

African (AFR)

AF:

0.0722

AC:

1905

AN:

26400

American (AMR)

AF:

0.0245

AC:

862

AN:

35203

Ashkenazi Jewish (ASJ)

AF:

0.0177

AC:

343

AN:

19381

East Asian (EAS)

AF:

0.0422

AC:

1275

AN:

30205

South Asian (SAS)

AF:

0.0118

AC:

638

AN:

54147

European-Finnish (FIN)

AF:

0.0186

AC:

752

AN:

40529

Middle Eastern (MID)

AF:

0.0116

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00951

AC:

8012

AN:

842054

Other (OTH)

AF:

0.0176

AC:

811

AN:

46094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

633

1266

1899

2532

3165

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

366

732

1098

1464

1830

<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:

0.0286

AC:

3183

AN:

111318

Hom.:

Cov.:

AF XY:

0.0263

AC XY:

880

AN XY:

33504

show subpopulations

African (AFR)

AF:

0.0700

AC:

2142

AN:

30603

American (AMR)

AF:

0.0173

AC:

181

AN:

10444

Ashkenazi Jewish (ASJ)

AF:

0.0185

AC:

AN:

2643

East Asian (EAS)

AF:

0.0433

AC:

153

AN:

3537

South Asian (SAS)

AF:

0.00845

AC:

AN:

2604

European-Finnish (FIN)

AF:

0.0149

AC:

AN:

5956

Middle Eastern (MID)

AF:

0.0230

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00956

AC:

508

AN:

53114

Other (OTH)

AF:

0.0225

AC:

AN:

1512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

114

228

342

456

570

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0200

Hom.:

1576

Bravo

AF:

0.0327

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.00831

AC:

ESP6500AA

AF:

0.0720

AC:

276

ESP6500EA

AF:

0.00847

AC:

ExAC

AF:

0.0211

AC:

2561

EpiCase

AF:

0.00840

EpiControl

AF:

0.00741

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Aug 08, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 17, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Mar 07, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DMD c.8734A>G (p.Asn2912Asp) results in a conservative amino acid change located in in a spectrin/alpha-actinin repeat (IPR018159) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.022 in 200085 control chromosomes in the gnomAD database, including 59 homozygotes and 1416 hemizygotes. The observed variant frequency is significantly higher than expected for a pathogenic variant in DMD causing Dystrophinopathies phenotype, strongly suggesting that the variant is benign. Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign (6x) and once as likely benign. Based on the evidence outlined above, the variant was classified as benign.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 21, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Asn2912Asp in exon 59 of DMD: This variant is not expected to have clinical si gnificance because it has been identified in 7.6% (802/10506) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs1800278).

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Duchenne muscular dystrophy

Uncertain:1Benign:3

May 18, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 01, 2017

Phosphorus, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 01, 1994

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:3

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Sep 11, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency

Benign:1

Aug 02, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Dilated cardiomyopathy 3B

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Cardiovascular phenotype

Benign:1

Oct 23, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0

.;T;T;T;.;.;T;.;.;T

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.61

T;.;.;.;.;T;.;T;T;.

MetaRNN

Benign

0.0015

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;.;.;.;.;.;.;.;.;.

PhyloP100

0.52

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.4

N;.;N;N;N;.;N;.;N;N

REVEL

Benign

0.062

Sift

Benign

0.17

T;.;D;T;D;.;T;.;T;D

Sift4G

Benign

0.19

T;T;T;T;T;T;T;T;T;T

Vest4

0.0

ClinPred

0.018

GERP RS

1.7

gMVP

0.16

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over