rs752332058

Variant names:

• chrX-31121883-CTCTGCCCAAATCA-C
• rs752332058
• ENST00000378723.7:c.1845_1857delTGATTTGGGCAGA

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PVS1_Moderate BP6 BS2

The ENST00000378723.7(DMD):​c.1845_1857delTGATTTGGGCAGA​(p.Asp615GlufsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000417 in 1,208,174 control chromosomes in the GnomAD database, including 4 homozygotes. There are 140 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (4 hom., 38 hem., cov: 23)
  • Exomes 𝑓: 0.00032 (0 hom. 102 hem.)
• Consequence: DMD ENST00000378723.7 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: 8.53
• Publications: 3 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

ENSG00000297249 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.033 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BP6: Variant X-31121883-CTCTGCCCAAATCA-C is Benign according to our data. Variant chrX-31121883-CTCTGCCCAAATCA-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 201754.
• BS2: High AC in GnomAd4 at 155 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.*23_*35delTGATTTGGGCAGA		3_prime_UTR_variant	Exon 79 of 79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.*23_*35delTGATTTGGGCAGA		3_prime_UTR_variant	Exon 79 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 155 AN: 112359 Hom.: 4 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000488

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000695

Gnomad OTH AF: 0.00132

GnomAD2 exomes AF: 0.000257 AC: 47 AN: 182672 AF XY: 0.000193

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000507

Gnomad NFE exome AF: 0.000454

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000318 AC: 349 AN: 1095815 Hom.: 0 AF XY: 0.000282 AC XY: 102 AN XY: 361619

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26323

American (AMR) AF: 0.0000284 AC: 1 AN: 35168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19342

East Asian (EAS) AF: 0.00 AC: 0 AN: 30185

South Asian (SAS) AF: 0.00 AC: 0 AN: 54093

European-Finnish (FIN) AF: 0.000718 AC: 29 AN: 40389

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.000358 AC: 301 AN: 840193

Other (OTH) AF: 0.000391 AC: 18 AN: 45990

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00138 AC: 155 AN: 112359 Hom.: 4 Cov.: 23 AF XY: 0.00110 AC XY: 38 AN XY: 34559

African (AFR) AF: 0.00 AC: 0 AN: 30938

American (AMR) AF: 0.00 AC: 0 AN: 10611

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3597

South Asian (SAS) AF: 0.00 AC: 0 AN: 2759

European-Finnish (FIN) AF: 0.000488 AC: 3 AN: 6147

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.000695 AC: 37 AN: 53231

Other (OTH) AF: 0.00132 AC: 2 AN: 1514

Alfa AF: 0.000218 Hom.: 2

Bravo AF: 0.00211

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:4

Jun 24, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asp1223fs in DMD has not been previously reported in individuals with musc ular dystrophy or cardiomyopathy, but has been identified in 22/47909 European c hromosomes, including 6 hemizygotes, by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). This variant is predicted to cause a frameshift , which alters the protein?s amino acid sequence beginning 28 amino acids upstre am of the C-terminus, leading to a termination codon 6 amino acids downstream. N onsense variants are generally predicted to cause absent protein; however when p resent in the last exon (as is the case for this variant), they are expected to result in a truncated protein. The established disease mechanism for DMD gene is loss of function and the role of other variants is less well understood. In add ition, this variant only affects the coding region on transcripts whose function al impact on skeletal and cardiac muscle is unclear (NM_004016.2, NM_004018.2, N M_004021.2; NM_004022.2, NM_004023.2). While the presence in hemizygous control individuals and lack of impact on coding region of the primary muscle dystrophi n isoform raises some doubt as to whether this variant can cause disease, the DM D gene has not been well sequenced in individuals with diagnoses other than Duch enne muscular dystrophy. Therefore the clinical significance of the p.Asp1223fs variant remains uncertain.

Sep 27, 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.*23_*35del13 is located in the untranslated mRNA region downstream of the termination codon. Though this variant also affects the coding region of other DMD transcripts (predictably disrupting their reading frame), the role of these affected dystrophin isoforms (e.g. Dp71 (NM_004016.2)) in disease currently is unclear. 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 0.00026 in 182672 control chromosomes. The observed variant frequency is approximately 23.33 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 benign. c.*23_*35del13 has been reported in the literature in 3 individuals affected with Dystrophinopathies, however without strong evidence for causality (Nigro 1994, Spitali 2009, Santos 2014). In addition, in one of these cases the patient also carried a pathogenic DMD variant in cis (deletion of exons 46-50) that could explain his muscular phenotype, though authors noted that the loss of other DMD isoforms (caused by this variant) may have a cumulative effect thereby explaining the patients mental impairment (Santos 2014). On the other hand, another DMD patient carrying the variant of interest, had no mental impairment (Nigro 1994). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign/likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.

Aug 25, 2017

GeneDx

Significance: Likely 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.

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely 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

not provided Benign:3

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DMD: BS2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Primary familial dilated cardiomyopathy Uncertain:1

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DMD-related disorder Benign:1

Nov 06, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Intellectual disability Benign:1

Jan 29, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Duchenne muscular dystrophy Benign:1

Oct 28, 2024

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
PhyloP100		8.5
Mutation Taster		=24/176	disease causing (long InDel)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs752332058; hg19: chrX-31140000; COSMIC: COSV58921107;