X-31679519-A-G

Position:

• chrX-31679519-A-G

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.7728T>C​(p.Asn2576=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 1,209,378 control chromosomes in the GnomAD database, including 16,866 homozygotes. There are 77,011 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (1216 hom., 5077 hem., cov: 23)
  • Exomes 𝑓: 0.20 (15650 hom. 71934 hem.)
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.08

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=-0.5).
• BP6: Variant X-31679519-A-G is Benign according to our data. Variant chrX-31679519-A-G is described in ClinVar as [Benign]. Clinvar id is 94776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-31679519-A-G is described in Lovd as [Benign]. Variant chrX-31679519-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.7728T>C	p.Asn2576=	synonymous_variant	53/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.7728T>C	p.Asn2576=	synonymous_variant	53/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.162 AC: 18031 AN: 111445 Hom.: 1217 Cov.: 23 AF XY: 0.151 AC XY: 5069 AN XY: 33657

Gnomad AFR AF: 0.0954

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.360

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.235

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.183

GnomAD3 exomes AF: 0.170 AC: 31122 AN: 183044 Hom.: 1926 AF XY: 0.173 AC XY: 11676 AN XY: 67558

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.0828

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.348

Gnomad SAS exome AF: 0.141

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.194

Gnomad OTH exome AF: 0.182

GnomAD4 exome AF: 0.199 AC: 218828 AN: 1097879 Hom.: 15650 Cov.: 31 AF XY: 0.198 AC XY: 71934 AN XY: 363295

Gnomad4 AFR exome AF: 0.0945

Gnomad4 AMR exome AF: 0.0902

Gnomad4 ASJ exome AF: 0.180

Gnomad4 EAS exome AF: 0.399

Gnomad4 SAS exome AF: 0.143

Gnomad4 FIN exome AF: 0.131

Gnomad4 NFE exome AF: 0.207

Gnomad4 OTH exome AF: 0.200

GnomAD4 genome AF: 0.162 AC: 18039 AN: 111499 Hom.: 1216 Cov.: 23 AF XY: 0.151 AC XY: 5077 AN XY: 33721

Gnomad4 AFR AF: 0.0954

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.174

Gnomad4 EAS AF: 0.360

Gnomad4 SAS AF: 0.137

Gnomad4 FIN AF: 0.115

Gnomad4 NFE AF: 0.197

Gnomad4 OTH AF: 0.188

Alfa AF: 0.185 Hom.: 2594

Bravo AF: 0.161

EpiCase AF: 0.203

EpiControl AF: 0.206

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 03, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2019	Variant summary: DMD c.7728T>C 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 0.17 in 204704 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.35 in the gnomAD database, including 584 homozygotes and 1751 hemizygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 30 fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophinopathies phenotype (0.011), strongly suggesting that the variant is a benign polymorphism. To our knowledge, no occurrence of c.7728T>C in individuals affected with Dystrophinopathies and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/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	Oct 29, 2014	p.Asn2576Asn in exon 53 of DMD: This variant is not expected to have clinical si gnificance because it has been identified in 20% (1364/6728) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs1801188). -

Duchenne muscular dystrophy Benign:3

Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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;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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 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	-0.50
CADD	Benign	7.0
DANN	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1801188; hg19: chrX-31697636; COSMIC: COSV58894615;