rs5030730

Variant names:

• chrX-32438372-G-A
• rs5030730
• NM_004006.3:c.3940C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004006.3(DMD):​c.3940C>T​(p.Arg1314*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: DMD NM_004006.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 3.30

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-32438372-G-A is Pathogenic according to our data. Variant chrX-32438372-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32438372-G-A is described in Lovd as [Pathogenic]. Variant chrX-32438372-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.3940C>T	p.Arg1314*	stop_gained	Exon 29 of 79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.3940C>T	p.Arg1314*	stop_gained	Exon 29 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Jun 22, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 10, 2018

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data. -

Jan 08, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 02, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay, and other loss-of-function variants have been reported downstream in HGMD; Published functional studies demonstrate that alternative splicing leads to different transcripts, some of which include exon skipping that bypasses the nonsense variant and correlates with a less severe phenotype (PMID: 11039581, 17041906); Not observed at significant frequency in large population cohorts (gnomAD); Based on the understanding of this genetic alteration, it may be amenable to nonsense read-through therapy that is currently available or in clinical trial; This variant is associated with the following publications: (PMID: 28116794, 17041906, 25525159, 16770791, 19959795, 25972034, 29604111, 28859693, 25612904, 28597072, 21972111, 29641567, 29581631, 35653365, 30833962, 11039581) -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Duchenne muscular dystrophy Pathogenic:2

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg1314*) in the DMD gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Becker muscular dystrophy (PMID: 11039581, 17041906, 19959795, 24292997, 29581631). ClinVar contains an entry for this variant (Variation ID: 11283). Studies have shown that this premature translational stop signal results in skipping of exon 29, but is expected to preserve the integrity of the reading-frame (PMID: 11039581, 17041906, 24292997). For these reasons, this variant has been classified as Pathogenic. -

Qualitative or quantitative defects of dystrophin Pathogenic:1

Jul 28, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DMD c.3940C>T (p.Arg1314X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 182875 control chromosomes (gnomAD). c.3940C>T has been reported in the literature in multiple hemizygous males affected with Becker Muscular Dystrophy, dilated cardiomyopathy, and elevated serum creatine kinase levels (e.g., Franz_2000, Ginjaar_2000, Deburgrave_2007, Torella_2010), and the variant has been shown to segregate with disease in related individuals. These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein, finding that alternative exon skipping restored the open reading frame in a portion of transcripts in patient tissue, however, the level of exon skipping varied across tissues and between patients, correlating with disease severity and phenotypic outcomes (e.g., Franz_2000, Ginjaar_2000, Deburgrave_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17041906, 10832829, 11039581, 19959795). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Becker muscular dystrophy Pathogenic:1

Oct 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	39
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.97	D
Vest4		0.92
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs5030730; hg19: chrX-32456489; COSMIC: COSV63740877;