chrX-32448508-G-A

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.3734C>T(p.Thr1245Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0116 in 1,206,985 control chromosomes in the GnomAD database, including 169 homozygotes. There are 4,240 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1245T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0099 ( 14 hom., 315 hem., cov: 23)

Exomes 𝑓: 0.012 ( 155 hom. 3925 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 6.09

Publications

7 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023860931).

BP6

Variant X-32448508-G-A is Benign according to our data. Variant chrX-32448508-G-A is described in ClinVar as Benign. ClinVar VariationId is 94604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0798 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.3734C>T	p.Thr1245Ile	missense_variant	Exon 27 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.3734C>T	p.Thr1245Ile	missense_variant	Exon 27 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes

AF:

0.00995

AC:

1105

AN:

111014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00212

Gnomad AMI

AF:

0.00872

Gnomad AMR

AF:

0.0401

Gnomad ASJ

AF:

0.0103

Gnomad EAS

AF:

0.000285

Gnomad SAS

AF:

0.00184

Gnomad FIN

AF:

0.00295

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0104

Gnomad OTH

AF:

0.0149

GnomAD2 exomes

AF:

0.0189

AC:

3452

AN:

182401

AF XY:

0.0144

show subpopulations

Gnomad AFR exome

AF:

0.00199

Gnomad AMR exome

AF:

0.0894

Gnomad ASJ exome

AF:

0.00820

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.00438

Gnomad NFE exome

AF:

0.00919

Gnomad OTH exome

AF:

0.0127

GnomAD4 exome

AF:

0.0118

AC:

12882

AN:

1095919

Hom.:

155

Cov.:

AF XY:

0.0108

AC XY:

3925

AN XY:

362543

show subpopulations

African (AFR)

AF:

0.00153

AC:

AN:

26226

American (AMR)

AF:

0.0823

AC:

2894

AN:

35149

Ashkenazi Jewish (ASJ)

AF:

0.00877

AC:

169

AN:

19278

East Asian (EAS)

AF:

0.0000664

AC:

AN:

30135

South Asian (SAS)

AF:

0.00288

AC:

156

AN:

54083

European-Finnish (FIN)

AF:

0.00370

AC:

150

AN:

40493

Middle Eastern (MID)

AF:

0.00291

AC:

AN:

4117

European-Non Finnish (NFE)

AF:

0.0107

AC:

9021

AN:

840495

Other (OTH)

AF:

0.00953

AC:

438

AN:

45943

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

457

914

1372

1829

2286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

390

780

1170

1560

1950

<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:

0.00995

AC:

1105

AN:

111066

Hom.:

Cov.:

AF XY:

0.00935

AC XY:

315

AN XY:

33694

show subpopulations

African (AFR)

AF:

0.00211

AC:

AN:

30757

American (AMR)

AF:

0.0400

AC:

417

AN:

10424

Ashkenazi Jewish (ASJ)

AF:

0.0103

AC:

AN:

2617

East Asian (EAS)

AF:

0.000286

AC:

AN:

3500

South Asian (SAS)

AF:

0.00184

AC:

AN:

2713

European-Finnish (FIN)

AF:

0.00295

AC:

AN:

6103

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0104

AC:

544

AN:

52547

Other (OTH)

AF:

0.0147

AC:

AN:

1499

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

110

146

183

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0103

Hom.:

633

Bravo

AF:

0.0143

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.0135

AC:

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.0109

AC:

ExAC

AF:

0.0139

AC:

1686

EpiCase

AF:

0.0104

EpiControl

AF:

0.00845

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Thr1245Ile in exon 27 of DMD: This variant is not expected to have clinical si gnificance because it has been identified in 1.1% (73/6728) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS/; dbSNP rs1800269). -

Mar 12, 2020

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.3734C>T (p.Thr1245Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.019 in 182401 control chromosomes, predominantly at a frequency of 0.089 within the Latino subpopulation in the gnomAD database, including 112 homozygotes and 971 hemizygotes. The observed variant frequency within Latino control individuals in the gnomAD database is significantly higher than expected for a pathogenic variant in DMD causing Dystrophinopathies phenotype, strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. Six ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 10, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 14, 2013

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. -

not provided

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 19, 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:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Benign:1

Apr 21, 2017

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dilated cardiomyopathy 3B

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiovascular phenotype

Benign:1

Jun 19, 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. -

Duchenne muscular dystrophy

Benign:1

Feb 03, 2025

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

0.16

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

.;T;.;.

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.89

D;.;D;D

MetaRNN

Benign

0.0024

T;T;T;T

MetaSVM

Benign

-0.96

PhyloP100

6.1

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.7

.;N;.;N

REVEL

Benign

0.12

Sift

Benign

0.044

.;D;.;D

Sift4G

Uncertain

0.049

D;D;D;D

Polyphen

0.83

.;P;.;.

Vest4

0.31

MPC

0.019

ClinPred

0.036

GERP RS

3.1

gMVP

0.15

Mutation Taster

=94/6

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