rs863225005

Positions:

• chrX-32342105-G-A
• chrX-32342105-G-C

Variant summary

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

The ENST00000357033.9(DMD):​c.5917C>T​(p.Gln1973Ter) 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 ENST00000357033.9 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.73

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-32342105-G-A is Pathogenic according to our data. Variant chrX-32342105-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 217206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32342105-G-A is described in Lovd as [Pathogenic]. Variant chrX-32342105-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.5917C>T	p.Gln1973Ter	stop_gained	41/79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.5917C>T	p.Gln1973Ter	stop_gained	41/79	1	NM_004006.3	ENSP00000354923	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 20, 2018	The DMD c.5917C>T; p.Gln1973Ter variant (rs863225005) has been described in individuals affected with Duchenne muscular dystrophy (DMD) (Buzin 2005, Flanigan 2009). It is listed in ClinVar (Variation ID: 217206) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, several downstream nonsense variants have been reported in individuals with DMD and are considered pathogenic (see link to UMD-DMD database and references therein). Based on available information, this variant is considered pathogenic. Pathogenic variants in DMD are inherited in an X-linked manner and are associated with Duchenne muscular dystrophy (MIM: 310200), Becker muscular dystrophy (MIM: 300376), and dilated cardiomyopathy (MIM: 302045). References: Link to UMD-DMD database: http://www.umd.be/DMD/4DACTION/W_DMDT1/10 Buzin C et al. Mutation rates in the dystrophin gene: a hotspot of mutation at a CpG dinucleotide. Hum Mutat. 2005 Feb;25(2):177-88. Flanigan K et al. Mutational spectrum of DMD mutations in dystrophinopathy patients: application of modern diagnostic techniques to a large cohort. Hum Mutat. 2009 Dec;30(12):1657-66. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2018	The Q1973X variant has been reported previously in association with dystrophinopathy, most often with Duchenne muscular dystrophy (Buzin et al., 2005; Flanigan et al., 2009). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q1973X variant is not observed in large population cohorts (Lek et al., 2016). -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 21, 2018	- -

Duchenne muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 30, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	A;A
Vest4		0.99
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs863225005; hg19: chrX-32360222;