X-31206663-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_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 benign 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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 5.38

Publications

14 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

Becker muscular dystrophy
Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
dilated cardiomyopathy 3B
Inheritance: XL Classification: DEFINITIVE Submitted by: Ambry Genetics
Duchenne and Becker muscular dystrophy
Inheritance: XL Classification: DEFINITIVE Submitted by: Myriad Women’s Health
Duchenne muscular dystrophy
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
progressive muscular dystrophy
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

DMD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 VariationId is 11282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.9568C>T	p.Arg3190*	stop_gained	Exon 66 of 79	ENST00000357033.9	NP_003997.2	P11532

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9 link	c.9568C>T	p.Arg3190*	stop_gained	Exon 66 of 79	1	NM_004006.3	ENSP00000354923.3		A0A075B6G3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000561

AC:

AN:

178134

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000368

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.16e-7

AC:

AN:

1091579

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

357241

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26299

American (AMR)

AF:

0.0000285

AC:

AN:

35106

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19321

East Asian (EAS)

AF:

0.00

AC:

AN:

30127

South Asian (SAS)

AF:

0.00

AC:

AN:

53434

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40440

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4125

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

836863

Other (OTH)

AF:

0.00

AC:

AN:

45864

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Duchenne muscular dystrophy

Pathogenic:5

Oct 17, 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.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. -

Dec 16, 2022

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PM2, PP5 -

Jul 01, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Apr 01, 2013

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:3

May 19, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 06, 2022

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 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) -

May 05, 2015

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuromuscular disease caused by qualitative or quantitative defects of dystrophin

Pathogenic:1

Feb 07, 2025

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.9568C>T (p.Arg3190X) 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. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.9568C>T has been reported in the literature in individuals affected with Dystrophinopathies (e.g., Zhong_2017, Cho_2016). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 27750387, 27593222). ClinVar contains an entry for this variant (Variation ID: 11282). 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

Oct 17, 2019

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dilated cardiomyopathy 3B

Pathogenic:1

Nov 08, 2017

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Pathogenic

0.97

PhyloP100

5.4

Vest4

0.98

ClinPred

0.98

GERP RS

4.3

PromoterAI

-0.030

Neutral

(source)

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over