X-32573814-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004006.3(DMD):c.1635A>G(p.Arg545=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,208,966 control chromosomes in the GnomAD database, including 6,324 homozygotes. There are 48,417 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (698 hom., 3924 hem., cov: 22)
  • Exomes 𝑓: 0.12 (5626 hom. 44493 hem.)
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.219

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-32573814-T-C is Benign according to our data. Variant chrX-32573814-T-C is described in ClinVar as [Benign]. Clinvar id is 94476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32573814-T-C is described in Lovd as [Benign]. Variant chrX-32573814-T-C is described in Lovd as [Pathogenic]. Variant chrX-32573814-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.219 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.1635A>G	p.Arg545=	synonymous_variant	14/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.1635A>G	p.Arg545=	synonymous_variant	14/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.125 AC: 14005 AN: 111659 Hom.: 699 Cov.: 22 AF XY: 0.116 AC XY: 3917 AN XY: 33837

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.0760

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.0143

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.0875

Gnomad MID AF: 0.163

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.126

GnomAD3 exomes AF: 0.107 AC: 19408 AN: 181905 Hom.: 791 AF XY: 0.110 AC XY: 7334 AN XY: 66537

Gnomad AFR exome AF: 0.160

Gnomad AMR exome AF: 0.0457

Gnomad ASJ exome AF: 0.155

Gnomad EAS exome AF: 0.0191

Gnomad SAS exome AF: 0.121

Gnomad FIN exome AF: 0.0985

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.121 AC: 132744 AN: 1097254 Hom.: 5626 Cov.: 31 AF XY: 0.123 AC XY: 44493 AN XY: 362870

Gnomad4 AFR exome AF: 0.161

Gnomad4 AMR exome AF: 0.0500

Gnomad4 ASJ exome AF: 0.158

Gnomad4 EAS exome AF: 0.0115

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.102

Gnomad4 NFE exome AF: 0.126

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.125 AC: 14006 AN: 111712 Hom.: 698 Cov.: 22 AF XY: 0.116 AC XY: 3924 AN XY: 33900

Gnomad4 AFR AF: 0.158

Gnomad4 AMR AF: 0.0757

Gnomad4 ASJ AF: 0.144

Gnomad4 EAS AF: 0.0140

Gnomad4 SAS AF: 0.120

Gnomad4 FIN AF: 0.0875

Gnomad4 NFE AF: 0.127

Gnomad4 OTH AF: 0.124

Alfa AF: 0.131 Hom.: 9656

Bravo AF: 0.126

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 17, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 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	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 29, 2014	p.Arg545Arg in exon 14 of DMD: This variant is not expected to have clinical sig nificance because it has been identified in 15% (586/3833) of African American c hromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/E VS/; dbSNP rs5927083). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 12, 2018	Variant summary: DMD c.1635A>G alters a non-conserved nucleotide resulting in a synonymous change. 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 0.11 in 198892 control chromosomes in the gnomAD database, including 879 homozygotes and 8224 hemizygotes. The observed variant frequency is approximately 10-fold above the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophiopathies phenotype (0.011), strongly suggesting that the variant is benign. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Duchenne muscular dystrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 28, 2017

- -

Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 20, 2017

- -

Dilated cardiomyopathy 3B Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 14, 2023

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	3.4
Dann	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs5927083; hg19: chrX-32591931; COSMIC: COSV55865224;