rs104894797

Positions:

• chrX-31206663-G-A

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.9568C>T​(p.Arg3190*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000916 in 1,091,579 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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: 24)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: DMD NM_004006.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 5.38

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 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-31206663-G-A is Pathogenic according to our data. Variant chrX-31206663-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-31206663-G-A is described in Lovd as [Pathogenic]. Variant chrX-31206663-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.9568C>T	p.Arg3190*	stop_gained	66/79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.9568C>T	p.Arg3190*	stop_gained	66/79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.16e-7 AC: 1 AN: 1091579 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 357241

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000285

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Duchenne muscular dystrophy Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Dec 16, 2022	PVS1, PM2, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 22, 2023	This sequence change creates a premature translational stop signal (p.Arg3190*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with Becker or Duchenne muscular dystrophy (PMID: 9544849, 27593222, 27750387). ClinVar contains an entry for this variant (Variation ID: 11282). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Becker muscular dystrophy (MIM#300376), Duchenne muscular dystrophy (MIM#310200) and dilated cardiomyopathy, 3B (DCM) (MIM#302045). (I) 0109 - This gene is associated with X-linked recessive disease. This gene is primarily associated with X-linked recessive disease relating to the muscular dystrophy phenotypes. In addition, females heterozygous for a DMD pathogenic variant may be affected depending on the pattern of X-inactivation and are also at increased risk for X-linked dominant DCM (OMIM, PMID: 26066469). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER / ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. While this variant has been identified in multiple individuals with Duchenne muscular dystrophy, it has also been reported as heterozygous in one individual with dilated cardiomyopathy 3B by a clinical diagnostic laboratory (ClinVar, PMIDs: 20485447, 23299919, 26968818, 30342905, 32559196). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 19, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a 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 for males; This variant is associated with the following publications: (PMID: 27750387, 27593222, 9544849, 28181689, 32559196, 25525159, 10094565, 15351422, 17041906, 17259292, 18652600, 19602481, 20485447, 31727011, 26968818, 34297739, 25007885, 16770791, 28152980, 26911353, 25612904, 23536893) -

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

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 17, 2019

- -

Dilated cardiomyopathy 3B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Nov 08, 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	38
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.97	D
Vest4		0.98
ClinPred		0.98	D
GERP RS		4.3

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: rs104894797; hg19: chrX-31224780; COSMIC: COSV58926460; COSMIC: COSV58926460;