rs752332058

Positions:

• chrX-31121883-CTCTGCCCAAATCA-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_Strong BS2

The NM_004021.3(DMD):​c.3669_3681delTGATTTGGGCAGA​(p.Asp1223fs) 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. 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 NM_004021.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 8.53

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 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. There are 6 pathogenic variants in the truncated region.
• BS2: High Homozygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3	c.*23_*35delTGATTTGGGCAGA		3_prime_UTR_variant	79/79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033	c.*23_*35delTGATTTGGGCAGA		3_prime_UTR_variant	79/79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 155 AN: 112359 Hom.: 4 Cov.: 23 AF XY: 0.00110 AC XY: 38 AN XY: 34559

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

GnomAD3 exomes AF: 0.000257 AC: 47 AN: 182672 Hom.: 0 AF XY: 0.000193 AC XY: 13 AN XY: 67352

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000718

Gnomad4 NFE exome AF: 0.000358

Gnomad4 OTH exome AF: 0.000391

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000488

Gnomad4 NFE AF: 0.000695

Gnomad4 OTH AF: 0.00132

Alfa AF: 0.000218 Hom.: 2

Bravo AF: 0.00211

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 27, 2019	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. -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 24, 2015	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. -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	DMD: BS2 -

Primary familial dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

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DMD-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 06, 2020

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). -

Duchenne muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs752332058; hg19: chrX-31140000;