NM_004006.3:c.6140A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBS1BS2_Supporting

The NM_004006.3(DMD):c.6140A>G(p.Gln2047Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000225 in 1,201,895 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 156 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. Q2047H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000090 ( 0 hom., 6 hem., cov: 23)

Exomes 𝑓: 0.00024 ( 0 hom. 150 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.75

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

DMD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0064988434).

BP6

Variant X-32287679-T-C is Benign according to our data. Variant chrX-32287679-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 290206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000899 (10/111249) while in subpopulation SAS AF = 0.00383 (10/2611). AF 95% confidence interval is 0.00208. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 10 XL,AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.6140A>G	p.Gln2047Arg	missense_variant	Exon 43 of 79	ENST00000357033.9	NP_003997.2	P11532

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9 link	c.6140A>G	p.Gln2047Arg	missense_variant	Exon 43 of 79	1	NM_004006.3	ENSP00000354923.3		A0A075B6G3

Frequencies

GnomAD3 genomes

AF:

0.0000899

AC:

AN:

111202

Hom.:

Cov.:

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:

0.00381

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000434

AC:

AN:

179797

AF XY:

0.000710

show subpopulations

Gnomad AFR exome

AF:

0.0000768

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000239

AC:

261

AN:

1090646

Hom.:

Cov.:

AF XY:

0.000421

AC XY:

150

AN XY:

356520

show subpopulations

African (AFR)

AF:

0.0000381

AC:

AN:

26248

American (AMR)

AF:

0.00

AC:

AN:

35046

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19292

East Asian (EAS)

AF:

0.00

AC:

AN:

30041

South Asian (SAS)

AF:

0.00473

AC:

252

AN:

53226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40311

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4107

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

836559

Other (OTH)

AF:

0.000175

AC:

AN:

45816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0000899

AC:

AN:

111249

Hom.:

Cov.:

AF XY:

0.000179

AC XY:

AN XY:

33443

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30682

American (AMR)

AF:

0.00

AC:

AN:

10401

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3560

South Asian (SAS)

AF:

0.00383

AC:

AN:

2611

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5891

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53043

Other (OTH)

AF:

0.00

AC:

AN:

1514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Hom

Variant carriers

<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:

0.0000778

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.000651

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Apr 29, 2021

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.6140A>G (p.Gln2047Arg) results in a conservative amino acid change located in the Central rod domain: Repeat 16 (Actin binding - ABD2, DOVE database) 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 0.00043 in 179797 control chromosomes, predominantly at a frequency of 0.0041 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 372 fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophinopathies phenotype (1.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.6140A>G in individuals affected with Dystrophinopathies and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Aug 10, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 21, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

Apr 18, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1

Dec 03, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DMD-related disorder

Benign:1

Jun 12, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Duchenne muscular dystrophy

Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Nov 18, 2020

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

0.073

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.82

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.21

.;T;.;.

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.61

T;.;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.0065

T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

1.7

PrimateAI

Benign

0.37

PROVEAN

Benign

0.21

.;N;.;N

REVEL

Benign

0.068

Sift

Benign

0.66

.;T;.;T

Sift4G

Benign

0.79

T;T;T;T

Polyphen

0.0

.;B;.;.

Vest4

0.10

MutPred

0.28

.;.;Gain of MoRF binding (P = 0.0105);Gain of MoRF binding (P = 0.0105);

MVP

0.42

MPC

0.016

ClinPred

0.011

GERP RS

3.2

gMVP

0.035

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

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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