rs193249735

chrX-32454654-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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

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=-0.78).
• 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 GnomAd at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.3603+8A>G		splice_region_variant, intron_variant		ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.3603+8A>G		splice_region_variant, intron_variant		1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.00682 AC: 738 AN: 108214 Hom.: 14 Cov.: 22 AF XY: 0.00579 AC XY: 180 AN XY: 31070

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.: 4 AF XY: 0.00125 AC XY: 69 AN XY: 55254

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.: 8 Cov.: 25 AF XY: 0.000576 AC XY: 191 AN XY: 331611

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.: 14 Cov.: 22 AF XY: 0.00579 AC XY: 180 AN XY: 31114

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.: 20

Bravo AF: 0.00765

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 21, 2012	- -
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, 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	-	- -

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

- -

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

- -

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. -

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

Invitae

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

Other links and lift over

dbSNP: rs193249735; hg19: chrX-32472771;