rs41303181

Positions:

chrX-32390194-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004006.3(DMD):c.4234-13A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0703 in 1,117,038 control chromosomes in the GnomAD database, including 2,092 homozygotes. There are 24,362 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.053 ( 183 hom., 1735 hem., cov: 23)

Exomes 𝑓: 0.072 ( 1909 hom. 22627 hem. )

Consequence

DMD
NM_004006.3 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -3.88

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BP6

Variant X-32390194-T-C is Benign according to our data. Variant chrX-32390194-T-C is described in ClinVar as [Benign]. Clinvar id is 94617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32390194-T-C is described in Lovd as [Benign]. Variant chrX-32390194-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.4234-13A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.4234-13A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004006.3	ENSP00000354923	P4

Frequencies

GnomAD3 genomes

AF:

0.0529

AC:

5884

AN:

111143

Hom.:

184

Cov.:

AF XY:

0.0519

AC XY:

1732

AN XY:

33341

show subpopulations

Gnomad AFR

AF:

0.00986

Gnomad AMI

AF:

0.0527

Gnomad AMR

AF:

0.0507

Gnomad ASJ

AF:

0.0914

Gnomad EAS

AF:

0.000846

Gnomad SAS

AF:

0.0311

Gnomad FIN

AF:

0.107

Gnomad MID

AF:

0.0795

Gnomad NFE

AF:

0.0744

Gnomad OTH

AF:

0.0641

GnomAD3 exomes

AF:

0.0607

AC:

10958

AN:

180502

Hom.:

269

AF XY:

0.0622

AC XY:

4080

AN XY:

65618

show subpopulations

Gnomad AFR exome

AF:

0.00848

Gnomad AMR exome

AF:

0.0499

Gnomad ASJ exome

AF:

0.0837

Gnomad EAS exome

AF:

0.000146

Gnomad SAS exome

AF:

0.0408

Gnomad FIN exome

AF:

0.117

Gnomad NFE exome

AF:

0.0743

Gnomad OTH exome

AF:

0.0679

GnomAD4 exome

AF:

0.0723

AC:

72692

AN:

1005841

Hom.:

1909

Cov.:

AF XY:

0.0778

AC XY:

22627

AN XY:

290821

show subpopulations

Gnomad4 AFR exome

AF:

0.00944

Gnomad4 AMR exome

AF:

0.0487

Gnomad4 ASJ exome

AF:

0.0872

Gnomad4 EAS exome

AF:

0.000505

Gnomad4 SAS exome

AF:

0.0429

Gnomad4 FIN exome

AF:

0.118

Gnomad4 NFE exome

AF:

0.0779

Gnomad4 OTH exome

AF:

0.0653

GnomAD4 genome

AF:

0.0529

AC:

5881

AN:

111197

Hom.:

183

Cov.:

AF XY:

0.0519

AC XY:

1735

AN XY:

33405

show subpopulations

Gnomad4 AFR

AF:

0.00984

Gnomad4 AMR

AF:

0.0503

Gnomad4 ASJ

AF:

0.0914

Gnomad4 EAS

AF:

0.000848

Gnomad4 SAS

AF:

0.0312

Gnomad4 FIN

AF:

0.107

Gnomad4 NFE

AF:

0.0745

Gnomad4 OTH

AF:

0.0639

Alfa

AF:

0.0702

Hom.:

763

Bravo

AF:

0.0484

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 04, 2019	Variant summary: DMD c.4234-13A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.061 in 197236 control chromosomes in the gnomAD database, including 306 homozygotes and 4517 hemizygotes. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.4234-13A>G in intron 30 of DMD: This variant is not expected to have clinical significance because it has been identified in 7.8% (524/6728) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs41303181). -

Dilated cardiomyopathy 3B

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 15, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Duchenne muscular dystrophy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

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

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 09, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.0050

DANN

Benign

0.32

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

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