rs201217593

Positions:

chrX-31177947-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5

The NM_004006.3(DMD):c.10247G>A(p.Trp3416Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,206,155 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

DMD
NM_004006.3 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:3

Conservation

PhyloP100: 7.31

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant X-31177947-C-T is Pathogenic according to our data. Variant chrX-31177947-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 374132.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=4, Pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.10247G>A	p.Trp3416Ter	stop_gained	71/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.10247G>A	p.Trp3416Ter	stop_gained	71/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes

AF:

0.0000360

AC:

AN:

110979

Hom.:

Cov.:

AF XY:

0.0000300

AC XY:

AN XY:

33301

show subpopulations

Gnomad AFR

AF:

0.0000655

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000282

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000223

AC:

AN:

179286

Hom.:

AF XY:

0.0000155

AC XY:

AN XY:

64508

show subpopulations

Gnomad AFR exome

AF:

0.000156

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000250

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000183

AC:

AN:

1095176

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360836

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000238

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000360

AC:

AN:

110979

Hom.:

Cov.:

AF XY:

0.0000300

AC XY:

AN XY:

33301

show subpopulations

Gnomad4 AFR

AF:

0.0000655

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000282

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000189

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000170

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 17, 2022	PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2022	Reported as a heterozygous variant in a patient with atherosclerosis in published literature; however, additional clinical information was not provided (Johnston et al., 2015); 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; 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; This variant is associated with the following publications: (PMID: 26046366) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 29, 2022	- -

Qualitative or quantitative defects of dystrophin

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Aug 07, 2023

Variant summary: DMD c.10247G>A (p.Trp3416X) results in a premature termination codon, predicted to cause an absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 2.2e-05 in 179286 control chromosomes (gnomAD) to include at-least one hemizygous individual with an unknown clinical history. To our knowledge, c.10247G>A has not been reported in the literature in individuals affected with Dystrophinopathies and no experimental evidence demonstrating an impact on protein function has been reported. However, it has been reported in at-least one individual with a negative personal/family history for muscle disease as part of the ClinSeq cohort that were selected for atherosclerosis but not for personal or family histories of any other phenotype (Johnston_2015). The following publication have been ascertained in the context of this evaluation (PMID: 26046366). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and pathogenic/likely pathogenic (n= 4). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Becker muscular dystrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 21, 2023

- -

Ptosis;C0015300:Proptosis;C0878544:Cardiomyopathy;C1850049:Clinodactyly of the 5th finger;C2051831:Pectus excavatum

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 03, 2014

- -

Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 16, 2021

The p.W3416* pathogenic mutation (also known as c.10247G>A), located in coding exon 71 of the DMD gene, results from a G to A substitution at nucleotide position 10247. This changes the amino acid from a tryptophan to a stop codon within coding exon 71. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Duchenne muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2023

This sequence change creates a premature translational stop signal (p.Trp3416*) 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). In addition, truncating variants in exon 71 (p.Pro3409Tyr*22, p.Thr3411Asn*22, and p.Leu3412Argfs*7) that result in partial in-frame exon skipping have been observed in individuals with clinical features of mild Becker muscular dystrophy (PMID: 17041906, 23536893). This variant is present in population databases (rs201217593, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DMD-related conditions. ClinVar contains an entry for this variant (Variation ID: 374132). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

0.99

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

A;A;A;A;A;A;D;D;D;D;D

Vest4

0.96

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over