Genetic Variant DMD:c.10262+1G>A (chrX-31177931-C-T) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PVS1_ModerateBP6BS1BS2

The NM_004006.3(DMD):c.10262+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,204,431 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 53 hemizygotes in GnomAD. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., 23 hem., cov: 23)

Exomes 𝑓: 0.000091 ( 0 hom. 30 hem. )

Consequence

DMD
NM_004006.3 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: 7.31

Publications

3 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:

ENSG00000297249 (HGNC:):

ENSG00000297249 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0035268583 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

BP6

Variant X-31177931-C-T is Benign according to our data. Variant chrX-31177931-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94433.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000619 (69/111532) while in subpopulation AFR AF = 0.00195 (60/30774). AF 95% confidence interval is 0.00155. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 69 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004006.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
DMD	NM_004006.3	MANE Select	c.10262+1G>A	splice_donor intron	N/A	NP_003997.2
DMD	NM_004009.3		c.10250+1G>A	splice_donor intron	N/A	NP_004000.1
DMD	NM_000109.4		c.10238+1G>A	splice_donor intron	N/A	NP_000100.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
DMD	ENST00000357033.9	TSL:1 MANE Select	c.10262+1G>A	splice_donor intron	N/A	ENSP00000354923.3
DMD	ENST00000378723.7	TSL:1	c.1058+1G>A	splice_donor intron	N/A	ENSP00000367997.3
DMD	ENST00000361471.8	TSL:1	c.1019+738G>A	intron	N/A	ENSP00000354464.4

Frequencies

GnomAD3 genomes

AF:

0.000628

AC:

AN:

111481

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00199

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000477

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000566

Gnomad OTH

AF:

0.000669

GnomAD2 exomes

AF:

0.000240

AC:

AN:

179061

AF XY:

0.000140

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.000479

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000728

Gnomad FIN exome

AF:

0.0000632

Gnomad NFE exome

AF:

0.0000501

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000906

AC:

AN:

1092899

Hom.:

Cov.:

AF XY:

0.0000836

AC XY:

AN XY:

358863

show subpopulations

African (AFR)

AF:

0.00179

AC:

AN:

26320

American (AMR)

AF:

0.000314

AC:

AN:

35066

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19330

East Asian (EAS)

AF:

0.00

AC:

AN:

30153

South Asian (SAS)

AF:

0.0000561

AC:

AN:

53431

European-Finnish (FIN)

AF:

0.0000248

AC:

AN:

40403

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4128

European-Non Finnish (NFE)

AF:

0.0000262

AC:

AN:

838099

Other (OTH)

AF:

0.000305

AC:

AN:

45969

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

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:

0.000619

AC:

AN:

111532

Hom.:

Cov.:

AF XY:

0.000681

AC XY:

AN XY:

33794

show subpopulations

African (AFR)

AF:

0.00195

AC:

AN:

30774

American (AMR)

AF:

0.000476

AC:

AN:

10505

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3545

South Asian (SAS)

AF:

0.00

AC:

AN:

2642

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6015

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0000566

AC:

AN:

52988

Other (OTH)

AF:

0.000661

AC:

AN:

1513

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.000239

Hom.:

Bravo

AF:

0.000975

ESP6500AA

AF:

0.00157

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000214

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Jan 15, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 27, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30415094, 23871722, 23352160, 26743743, 26990548, 32013268, 30275481)

not specified

Benign:2

Feb 09, 2022

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.10262+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00024 in 179061 control chromosomes (including 9 hemizygotes), predominantly at a frequency of 0.0017 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 154-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 African or African-American origin. c.10262+1G>A has been reported in the literature in male individuals affected with dystrophinopathies, autism spectrum disorder and atrial fibrillation and also, in women with sudden death and peripartum cardiomyopathy (Lim_2013, Kim_2016, Ware_2016, Scheiper_2018, Vad_2020). These reports do 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. Five ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.

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

Duchenne muscular dystrophy

Benign:2

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dilated cardiomyopathy 3B

Uncertain:1

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PP3. This variant was detected in hemizygous state.

Cardiovascular phenotype

Benign:1

Jan 09, 2019

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Pathogenic

0.99

PhyloP100

7.3

GERP RS

4.9

PromoterAI

-0.078

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=3/97

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.94

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.94

Position offset: 1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over