rs41303181

Positions:

• chrX-32390194-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -3.88

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 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	UniProt
DMD	NM_004006.3	c.4234-13A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000357033.9

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0529 AC: 5884 AN: 111143 Hom.: 184 Cov.: 23 AF XY: 0.0519 AC XY: 1732 AN XY: 33341

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

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.: 22 AF XY: 0.0778 AC XY: 22627 AN XY: 290821

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.: 23 AF XY: 0.0519 AC XY: 1735 AN XY: 33405

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	Eurofins Ntd Llc (ga)	Jan 21, 2016	- -
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). -
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. -

Dilated cardiomyopathy 3B Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
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. -

Duchenne muscular dystrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 15, 2023

- -

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

Other links and lift over

dbSNP: rs41303181; hg19: chrX-32408311; COSMIC: COSV63750397;