rs727503828

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3BP6BS2

The NM_004006.3(DMD):c.5010G>T(p.Trp1670Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00042 in 1,208,544 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 136 hemizygotes in GnomAD. In-silico tool predicts a pathogenic 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. W1670G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., 10 hem., cov: 22)

Exomes 𝑓: 0.00043 ( 0 hom. 126 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 7.79

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

DMD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.803

BP6

Variant X-32365035-C-A is Benign according to our data. Variant chrX-32365035-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166757.

BS2

High AC in GnomAd4 at 34 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.5010G>T	p.Trp1670Cys	missense_variant	Exon 35 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.5010G>T	p.Trp1670Cys	missense_variant	Exon 35 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes

AF:

0.000307

AC:

AN:

110828

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000656

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:

0.000342

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000566

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000213

AC:

AN:

183125

AF XY:

0.000133

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000250

Gnomad NFE exome

AF:

0.000404

Gnomad OTH exome

AF:

0.000442

GnomAD4 exome

AF:

0.000431

AC:

473

AN:

1097716

Hom.:

Cov.:

AF XY:

0.000347

AC XY:

126

AN XY:

363202

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26382

American (AMR)

AF:

0.0000284

AC:

AN:

35194

Ashkenazi Jewish (ASJ)

AF:

0.0000516

AC:

AN:

19375

East Asian (EAS)

AF:

0.00

AC:

AN:

30160

South Asian (SAS)

AF:

0.00

AC:

AN:

54139

European-Finnish (FIN)

AF:

0.000395

AC:

AN:

40520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.000523

AC:

440

AN:

841743

Other (OTH)

AF:

0.000326

AC:

AN:

46069

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

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

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:

0.000307

AC:

AN:

110828

Hom.:

Cov.:

AF XY:

0.000303

AC XY:

AN XY:

33040

show subpopulations

African (AFR)

AF:

0.0000656

AC:

AN:

30510

American (AMR)

AF:

0.00

AC:

AN:

10327

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2638

East Asian (EAS)

AF:

0.00

AC:

AN:

3518

South Asian (SAS)

AF:

0.00

AC:

AN:

2612

European-Finnish (FIN)

AF:

0.000342

AC:

AN:

5853

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.000566

AC:

AN:

52958

Other (OTH)

AF:

0.00

AC:

AN:

1491

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000427

Hom.:

Bravo

AF:

0.000321

ExAC

AF:

0.000222

AC:

EpiCase

AF:

0.000655

EpiControl

AF:

0.000297

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 29, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DMD: BS2 -

Mar 28, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30564623, 14695533) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:1

Sep 16, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Trp1670Cys variant in DMD has been identified in one individual with DMD ( Hofstra 2004). It has also been identified in 23/47847 European chromosomes, inc luding 4 hemizygotes, by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs727503828). Computational prediction tools and conserv ation analysis suggest that this variant may impact the protein, though this inf ormation is not predictive enough to determine pathogenicity. In summary, the cl inical significance of the p.Trp1670Cys variant is uncertain. -

Feb 05, 2024

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.5010G>T (p.Trp1670Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 1208544 control chromosomes, including 136 hemizygotes. The observed variant frequency is approximately 38 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 benign. c.5010G>T has been reported in at-least one gender unspecified individual affected with DMD and a non-informative genotype (example: Hofstra_2004). This report does not provide unequivocal conclusions about association of the variant with Dystrophinopathies. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29016797, 14695533). ClinVar contains an entry for this variant (Variation ID: 166757). Based on the evidence outlined above, the variant was classified as likely benign. -

Duchenne muscular dystrophy

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Mar 02, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

.;T;.;.;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;.;D;D;D

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.80

D;D;D;D;D

MetaSVM

Benign

-0.45

PhyloP100

7.8

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-6.5

.;D;.;D;D

REVEL

Uncertain

0.57

Sift

Uncertain

0.0030

.;D;.;D;D

Sift4G

Uncertain

0.010

D;D;D;D;D

Polyphen

1.0

.;D;.;.;.

Vest4

0.84

MutPred

0.70

.;.;Gain of catalytic residue at L1671 (P = 0.0224);Gain of catalytic residue at L1671 (P = 0.0224);.;

MVP

0.90

MPC

0.10

ClinPred

0.59

GERP RS

5.5

gMVP

0.66

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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