rs863225011

Positions:

• chrX-31627852-G-A
• chrX-31627852-G-C
• chrX-31627852-G-T

Variant summary

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

The ENST00000357033.9(DMD):​c.8038C>T​(p.Arg2680Ter) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R2680R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., 0 hem., cov: 22)
  • Failed GnomAD Quality Control
• Consequence: DMD ENST00000357033.9 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.945

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-31627852-G-A is Pathogenic according to our data. Variant chrX-31627852-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 217213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-31627852-G-A is described in Lovd as [Pathogenic]. Variant chrX-31627852-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3	c.8038C>T	p.Arg2680Ter	stop_gained	55/79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.8038C>T	p.Arg2680Ter	stop_gained	55/79	1	NM_004006.3	ENSP00000354923	P4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 111035 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33271 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 111035 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33271

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: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 20, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 13, 2022	- -

Duchenne muscular dystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	This sequence change creates a premature translational stop signal at codon 2680 (p.Arg2680*) of 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 (Aartsma‐Rus et al). This variant has been reported in individuals affected with Duchenne muscular dystrophy (DMD) (Magri, Francesca, et al,Tuffery-Giraud, Sylvie, et al). This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change in DMD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. For these reasons, this variant has been classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 10, 2022	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 217213). This premature translational stop signal has been observed in individuals with Duchenne muscular dystrophy (DMD) (PMID: 15351422, 16770791, 17041906, 18583217, 19835634, 19937601, 21396098, 25612904, 25636106). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg2680*) 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). -

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

Jun 17, 2019

Variant summary: DMD c.8038C>T (p.Arg2680X) 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. Large deletions downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 174421 control chromosomes. c.8038C>T has been reported in the literature in multiple individuals affected with Duchenne muscular dystrophy (eg. Tuffery-Giraud_2004, Flanigan_2011, Magri_2011, Connolly_2015, Ma_2018, Xu_2018). 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. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
Vest4		0.94, 0.94, 0.96, 0.95
ClinPred		1.0	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs863225011; hg19: chrX-31645969;