rs147931243

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_004006.3(DMD):c.2381-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000693 in 1,203,022 control chromosomes in the GnomAD database, including 8 homozygotes. There are 271 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., 23 hem., cov: 24)

Exomes 𝑓: 0.00070 ( 8 hom. 248 hem. )

Consequence

DMD
NM_004006.3 splice_region, intron

Scores

Splicing: ADA: 0.006386

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.22

Publications

2 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:

ENSG00000297605 (HGNC:):

ENSG00000297605 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.29).

BP6

Variant X-32491521-A-G is Benign according to our data. Variant chrX-32491521-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000579 (65/112197) while in subpopulation EAS AF = 0.0173 (62/3590). AF 95% confidence interval is 0.0138. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High AC in GnomAd4 at 65 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.2381-3T>C		splice_region_variant, intron_variant	Intron 19 of 78	ENST00000357033.9	NP_003997.2	P11532

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9 link	c.2381-3T>C		splice_region_variant, intron_variant	Intron 19 of 78	1	NM_004006.3	ENSP00000354923.3		A0A075B6G3

Frequencies

GnomAD3 genomes

AF:

0.000580

AC:

AN:

112143

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:

0.0172

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000375

Gnomad OTH

AF:

0.000663

GnomAD2 exomes

AF:

0.00151

AC:

259

AN:

171091

AF XY:

0.00146

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00164

Gnomad EAS exome

AF:

0.0186

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000465

GnomAD4 exome

AF:

0.000705

AC:

769

AN:

1090825

Hom.:

Cov.:

AF XY:

0.000695

AC XY:

248

AN XY:

356979

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26164

American (AMR)

AF:

0.00

AC:

AN:

34953

Ashkenazi Jewish (ASJ)

AF:

0.000724

AC:

AN:

19331

East Asian (EAS)

AF:

0.0241

AC:

721

AN:

29911

South Asian (SAS)

AF:

0.000113

AC:

AN:

53278

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39690

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4041

European-Non Finnish (NFE)

AF:

0.0000131

AC:

AN:

837679

Other (OTH)

AF:

0.000371

AC:

AN:

45778

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

120

150

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:

0.000579

AC:

AN:

112197

Hom.:

Cov.:

AF XY:

0.000669

AC XY:

AN XY:

34371

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30907

American (AMR)

AF:

0.00

AC:

AN:

10539

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.0173

AC:

AN:

3590

South Asian (SAS)

AF:

0.00

AC:

AN:

2713

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6108

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

53257

Other (OTH)

AF:

0.000655

AC:

AN:

1527

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.000434

Hom.:

Bravo

AF:

0.000695

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Sep 14, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 02, 2016

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. -

Nov 04, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

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

Nov 06, 2017

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dilated cardiomyopathy 3B

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B

Benign:1

Jul 06, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

Cardiovascular phenotype

Benign:1

May 17, 2019

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

BayesDel_noAF

Benign

-0.29

CADD

Benign

8.9

(source)

DANN

Benign

0.95

PhyloP100

2.2

Mutation Taster

=90/10

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0064

dbscSNV1_RF

Benign

0.062

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