rs398123953

chrX-32389644-G-AchrX-32389644-G-C

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.4375C>T(p.Arg1459Ter) variant causes a stop gained change involving the alteration of a 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R1459R) has been classified as Likely benign. 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:5
• Conservation: PhyloP100: 7.79

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-32389644-G-A is Pathogenic according to our data. Variant chrX-32389644-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 94623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32389644-G-A is described in Lovd as [Pathogenic]. Variant chrX-32389644-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.4375C>T	p.Arg1459Ter	stop_gained	32/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.4375C>T	p.Arg1459Ter	stop_gained	32/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Duchenne muscular dystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	This sequence change creates a premature translational stop signal (p.Arg1459*) in the DMD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DMD are known to be pathogenic (PMID: 16770791, 25007885). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with DMD-related dystrophinopathies (PMID: 7611292, 9067763, 16834926, 21515508, 23453023, 27593222). ClinVar contains an entry for this variant (Variation ID: 94623). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 17, 2014	- -

Qualitative or quantitative defects of dystrophin Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 02, 2020

Variant summary: DMD c.4375C>T (p.Arg1459X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 182456 control chromosomes. c.4375C>T has been reported in the literature in individuals affected with Dystrophinopathies (example, Prior_1995, Mah_2011, Cho_2017, Wang_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in absent expression of Dystrophin C-terminus protein (example, Wang_2019). Two 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 12, 2021

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 07, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	40
Dann	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A
Vest4		0.94
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs398123953; hg19: chrX-32407761; COSMIC: COSV63738314;