X-32390194-T-C

Variant names:

• chrX-32390194-T-C
• rs41303181
• NM_004006.3:c.4234-13A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004006.3(DMD):​c.4234-13A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0703 in 1,117,038 control chromosomes in the GnomAD database, including 2,092 homozygotes. There are 24,362 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (183 hom., 1735 hem., cov: 23)
  • Exomes 𝑓: 0.072 (1909 hom. 22627 hem.)
• Consequence: DMD NM_004006.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -3.88
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant X-32390194-T-C is Benign according to our data. Variant chrX-32390194-T-C is described in ClinVar as Benign. ClinVar VariationId is 94617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.4234-13A>G		intron_variant	Intron 30 of 78	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.4234-13A>G		intron_variant	Intron 30 of 78	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes AF: 0.0529 AC: 5884 AN: 111143 Hom.: 184 Cov.: 23

Gnomad AFR AF: 0.00986

Gnomad AMI AF: 0.0527

Gnomad AMR AF: 0.0507

Gnomad ASJ AF: 0.0914

Gnomad EAS AF: 0.000846

Gnomad SAS AF: 0.0311

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0795

Gnomad NFE AF: 0.0744

Gnomad OTH AF: 0.0641

GnomAD2 exomes AF: 0.0607 AC: 10958 AN: 180502 AF XY: 0.0622

Gnomad AFR exome AF: 0.00848

Gnomad AMR exome AF: 0.0499

Gnomad ASJ exome AF: 0.0837

Gnomad EAS exome AF: 0.000146

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.0743

Gnomad OTH exome AF: 0.0679

GnomAD4 exome AF: 0.0723 AC: 72692 AN: 1005841 Hom.: 1909 Cov.: 22 AF XY: 0.0778 AC XY: 22627 AN XY: 290821

African (AFR) AF: 0.00944 AC: 233 AN: 24688

American (AMR) AF: 0.0487 AC: 1708 AN: 35048

Ashkenazi Jewish (ASJ) AF: 0.0872 AC: 1640 AN: 18805

East Asian (EAS) AF: 0.000505 AC: 15 AN: 29703

South Asian (SAS) AF: 0.0429 AC: 2226 AN: 51919

European-Finnish (FIN) AF: 0.118 AC: 4768 AN: 40252

Middle Eastern (MID) AF: 0.0579 AC: 226 AN: 3903

European-Non Finnish (NFE) AF: 0.0779 AC: 59072 AN: 758551

Other (OTH) AF: 0.0653 AC: 2804 AN: 42972

GnomAD4 genome AF: 0.0529 AC: 5881 AN: 111197 Hom.: 183 Cov.: 23 AF XY: 0.0519 AC XY: 1735 AN XY: 33405

African (AFR) AF: 0.00984 AC: 302 AN: 30688

American (AMR) AF: 0.0503 AC: 523 AN: 10403

Ashkenazi Jewish (ASJ) AF: 0.0914 AC: 241 AN: 2637

East Asian (EAS) AF: 0.000848 AC: 3 AN: 3536

South Asian (SAS) AF: 0.0312 AC: 82 AN: 2630

European-Finnish (FIN) AF: 0.107 AC: 636 AN: 5936

Middle Eastern (MID) AF: 0.0826 AC: 18 AN: 218

European-Non Finnish (NFE) AF: 0.0745 AC: 3944 AN: 52963

Other (OTH) AF: 0.0639 AC: 96 AN: 1503

Alfa AF: 0.0561 Hom.: 806

Bravo AF: 0.0484

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2016

Eurofins Ntd Llc (ga)

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

c.4234-13A>G in intron 30 of DMD: This variant is not expected to have clinical significance because it has been identified in 7.8% (524/6728) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs41303181). -

Jan 22, 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. -

Mar 04, 2019

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.4234-13A>G 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 0.061 in 197236 control chromosomes in the gnomAD database, including 306 homozygotes and 4517 hemizygotes. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -

Dilated cardiomyopathy 3B Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not provided Benign:2

Nov 15, 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

- -

Duchenne muscular dystrophy Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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 09, 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	-0.97
CADD	Benign	0.0050
DANN	Benign	0.32
PhyloP100		-3.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41303181; hg19: chrX-32408311;