X-32545146-A-G

Position:

chrX-32545146-A-G

Variant summary

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

The ENST00000357033.9(DMD):c.2168+13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,203,283 control chromosomes in the GnomAD database, including 31,458 homozygotes. There are 103,963 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 4627 hom., 10534 hem., cov: 23)

Exomes 𝑓: 0.26 ( 26831 hom. 93429 hem. )

Consequence

DMD
ENST00000357033.9 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.890

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=-0.83).

BP6

Variant X-32545146-A-G is Benign according to our data. Variant chrX-32545146-A-G is described in ClinVar as [Benign]. Clinvar id is 94495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32545146-A-G is described in Lovd as [Benign]. Variant chrX-32545146-A-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.526 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.2168+13T>C		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.2168+13T>C		intron_variant		1	NM_004006.3	ENSP00000354923	P4

Frequencies

GnomAD3 genomes

AF:

0.323

AC:

35839

AN:

111110

Hom.:

4620

Cov.:

AF XY:

0.315

AC XY:

10510

AN XY:

33388

show subpopulations

Gnomad AFR

AF:

0.468

Gnomad AMI

AF:

0.151

Gnomad AMR

AF:

0.337

Gnomad ASJ

AF:

0.272

Gnomad EAS

AF:

0.545

Gnomad SAS

AF:

0.315

Gnomad FIN

AF:

0.262

Gnomad MID

AF:

0.264

Gnomad NFE

AF:

0.234

Gnomad OTH

AF:

0.320

GnomAD3 exomes

AF:

0.313

AC:

56257

AN:

180013

Hom.:

6538

AF XY:

0.299

AC XY:

19481

AN XY:

65237

show subpopulations

Gnomad AFR exome

AF:

0.474

Gnomad AMR exome

AF:

0.397

Gnomad ASJ exome

AF:

0.273

Gnomad EAS exome

AF:

0.537

Gnomad SAS exome

AF:

0.306

Gnomad FIN exome

AF:

0.279

Gnomad NFE exome

AF:

0.232

Gnomad OTH exome

AF:

0.289

GnomAD4 exome

AF:

0.260

AC:

284460

AN:

1092120

Hom.:

26831

Cov.:

AF XY:

0.261

AC XY:

93429

AN XY:

358552

show subpopulations

Gnomad4 AFR exome

AF:

0.475

Gnomad4 AMR exome

AF:

0.394

Gnomad4 ASJ exome

AF:

0.269

Gnomad4 EAS exome

AF:

0.523

Gnomad4 SAS exome

AF:

0.304

Gnomad4 FIN exome

AF:

0.278

Gnomad4 NFE exome

AF:

0.233

Gnomad4 OTH exome

AF:

0.281

GnomAD4 genome

AF:

0.323

AC:

35881

AN:

111163

Hom.:

4627

Cov.:

AF XY:

0.315

AC XY:

10534

AN XY:

33449

show subpopulations

Gnomad4 AFR

AF:

0.468

Gnomad4 AMR

AF:

0.338

Gnomad4 ASJ

AF:

0.272

Gnomad4 EAS

AF:

0.547

Gnomad4 SAS

AF:

0.313

Gnomad4 FIN

AF:

0.262

Gnomad4 NFE

AF:

0.234

Gnomad4 OTH

AF:

0.327

Alfa

AF:

0.259

Hom.:

22514

Bravo

AF:

0.342

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 12, 2018	Variant summary: DMD c.2168+13T>C 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. The variant allele was found at a frequency of 0.32 in 82561 control chromosomes in the ExAC database, including 3112 homozygotes. The observed variant frequency is approximately 28.65 fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophiopathies phenotype (0.011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2168+13T>C in individuals affected with Dystrophiopathies and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.2168+13T>C in intron 17 of DMD: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence. It has been identified in 47.4% (1816/3833) of African American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS; dbSNP rs228373). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 24, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2013	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. -

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

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

-0.83

CADD

Benign

DANN

Benign

0.78

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

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