X-32454654-T-C

Position:

chrX-32454654-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004006.3(DMD):c.3603+8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,158,149 control chromosomes in the GnomAD database, including 22 homozygotes. There are 371 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0068 ( 14 hom., 180 hem., cov: 22)

Exomes 𝑓: 0.00068 ( 8 hom. 191 hem. )

Consequence

DMD
NM_004006.3 splice_region, intron

Scores

Splicing: ADA: 0.0006101

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.860

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:

DMD (HGNC:):

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=-0.78).

BP6

Variant X-32454654-T-C is Benign according to our data. Variant chrX-32454654-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 94600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32454654-T-C is described in Lovd as [Benign]. Variant chrX-32454654-T-C is described in Lovd as [Likely_benign]. Variant chrX-32454654-T-C is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00681 (737/108248) while in subpopulation AFR AF= 0.0233 (702/30113). AF 95% confidence interval is 0.0219. There are 14 homozygotes in gnomad4. There are 180 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.3603+8A>G		splice_region_variant, intron_variant		ENST00000357033.9	NP_003997.2	P11532

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.3603+8A>G		splice_region_variant, intron_variant		1	NM_004006.3	ENSP00000354923.3		A0A075B6G3

Frequencies

GnomAD3 genomes

AF:

0.00682

AC:

738

AN:

108214

Hom.:

Cov.:

AF XY:

0.00579

AC XY:

180

AN XY:

31070

show subpopulations

Gnomad AFR

AF:

0.0234

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00248

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000193

Gnomad OTH

AF:

0.00619

GnomAD3 exomes

AF:

0.00204

AC:

325

AN:

159242

Hom.:

AF XY:

0.00125

AC XY:

AN XY:

55254

show subpopulations

Gnomad AFR exome

AF:

0.0243

Gnomad AMR exome

AF:

0.00114

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:

0.00

Gnomad OTH exome

AF:

0.00104

GnomAD4 exome

AF:

0.000679

AC:

713

AN:

1049901

Hom.:

Cov.:

AF XY:

0.000576

AC XY:

191

AN XY:

331611

show subpopulations

Gnomad4 AFR exome

AF:

0.0235

Gnomad4 AMR exome

AF:

0.00156

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000101

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000613

Gnomad4 OTH exome

AF:

0.00160

GnomAD4 genome

AF:

0.00681

AC:

737

AN:

108248

Hom.:

Cov.:

AF XY:

0.00579

AC XY:

180

AN XY:

31114

show subpopulations

Gnomad4 AFR

AF:

0.0233

Gnomad4 AMR

AF:

0.00248

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000193

Gnomad4 OTH

AF:

0.00611

Alfa

AF:

0.00386

Hom.:

Bravo

AF:

0.00765

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 21, 2012	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 30, 2017	- -

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

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 10, 2017

- -

Dilated cardiomyopathy 3B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 25, 2021

- -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

- -

Duchenne muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

8.3

DANN

Benign

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00061

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.070

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