NM_004006.3:c.9649+15T>C

Variant names:

• chrX-31206567-A-G
• rs2293668
• NM_004006.3:c.9649+15T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_004006.3(DMD):​c.9649+15T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (27532 hom., 27775 hem., cov: 23)
  • Exomes 𝑓: 0.87 (279734 hom. 299840 hem.)
  • Failed GnomAD Quality Control
• Consequence: DMD NM_004006.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.472
• Publications: 11 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant X-31206567-A-G is Benign according to our data. Variant chrX-31206567-A-G is described in ClinVar as Benign. ClinVar VariationId is 94854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.9649+15T>C		intron_variant	Intron 66 of 78	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.9649+15T>C		intron_variant	Intron 66 of 78	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes AF: 0.840 AC: 92965 AN: 110693 Hom.: 27535 Cov.: 23

Gnomad AFR AF: 0.734

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.908

Gnomad ASJ AF: 0.863

Gnomad EAS AF: 0.803

Gnomad SAS AF: 0.819

Gnomad FIN AF: 0.888

Gnomad MID AF: 0.878

Gnomad NFE AF: 0.883

Gnomad OTH AF: 0.859

GnomAD2 exomes AF: 0.867 AC: 148595 AN: 171412 AF XY: 0.870

Gnomad AFR exome AF: 0.737

Gnomad AMR exome AF: 0.922

Gnomad ASJ exome AF: 0.862

Gnomad EAS exome AF: 0.802

Gnomad FIN exome AF: 0.883

Gnomad NFE exome AF: 0.884

Gnomad OTH exome AF: 0.887

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.874 AC: 938413 AN: 1073286 Hom.: 279734 Cov.: 23 AF XY: 0.874 AC XY: 299840 AN XY: 343168

African (AFR) AF: 0.730 AC: 18921 AN: 25908

American (AMR) AF: 0.921 AC: 32139 AN: 34912

Ashkenazi Jewish (ASJ) AF: 0.859 AC: 16477 AN: 19188

East Asian (EAS) AF: 0.815 AC: 24446 AN: 30001

South Asian (SAS) AF: 0.835 AC: 44081 AN: 52820

European-Finnish (FIN) AF: 0.879 AC: 35437 AN: 40324

Middle Eastern (MID) AF: 0.852 AC: 3465 AN: 4067

European-Non Finnish (NFE) AF: 0.883 AC: 724314 AN: 820742

Other (OTH) AF: 0.863 AC: 39133 AN: 45324

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.840 AC: 93027 AN: 110750 Hom.: 27532 Cov.: 23 AF XY: 0.843 AC XY: 27775 AN XY: 32960

African (AFR) AF: 0.734 AC: 22375 AN: 30492

American (AMR) AF: 0.908 AC: 9463 AN: 10418

Ashkenazi Jewish (ASJ) AF: 0.863 AC: 2279 AN: 2640

East Asian (EAS) AF: 0.804 AC: 2816 AN: 3504

South Asian (SAS) AF: 0.819 AC: 2128 AN: 2597

European-Finnish (FIN) AF: 0.888 AC: 5192 AN: 5849

Middle Eastern (MID) AF: 0.880 AC: 191 AN: 217

European-Non Finnish (NFE) AF: 0.883 AC: 46665 AN: 52846

Other (OTH) AF: 0.861 AC: 1302 AN: 1512

Alfa AF: 0.865 Hom.: 152131

Bravo AF: 0.839

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.9649+15T>C in intron 66 of DMD: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence. It has been identified in 26.6% (1020/3830) of African American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS; dbSNP rs2293668). -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 12, 2018

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.9649+15T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.88 in 74144 control chromosomes, suggesting that it is the major allele and therefore benign. The observed variant frequency is approximately 79.032 fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophiopathies phenotype (0.011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.9649+15T>C in individuals affected with Dystrophiopathies and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 08, 2014

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. -

Dilated cardiomyopathy 3B Benign:2

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. -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Nov 21, 2024

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

- -

Duchenne muscular dystrophy Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

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

Aug 08, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.6
DANN	Benign	0.76
PhyloP100		0.47
PromoterAI		-0.0042	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2293668; hg19: chrX-31224684; COSMIC: COSV58941457; COSMIC: COSV58941457;