rs112516305

chrX-31773981-G-AchrX-31773981-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_004006.3(DMD):c.7521C>T(p.Asn2507=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000383 in 1,205,000 control chromosomes in the GnomAD database, including 1 homozygotes. There are 141 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., 6 hem., cov: 21)
  • Exomes 𝑓: 0.00040 (1 hom. 135 hem.)
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: -0.178

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant X-31773981-G-A is Benign according to our data. Variant chrX-31773981-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 284947.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=4, Benign=1}.
• BP7: Synonymous conserved (PhyloP=-0.178 with no splicing effect.
• BS2: High Hemizygotes in GnomAd at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.7521C>T	p.Asn2507=	synonymous_variant	51/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.7521C>T	p.Asn2507=	synonymous_variant	51/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 20 AN: 108750 Hom.: 0 Cov.: 21 AF XY: 0.000193 AC XY: 6 AN XY: 31086

Gnomad AFR AF: 0.000168

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000285

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000235 AC: 43 AN: 182920 Hom.: 0 AF XY: 0.000193 AC XY: 13 AN XY: 67532

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000491

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000402 AC: 441 AN: 1096250 Hom.: 1 Cov.: 30 AF XY: 0.000373 AC XY: 135 AN XY: 361710

Gnomad4 AFR exome AF: 0.000190

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000502

Gnomad4 OTH exome AF: 0.000217

GnomAD4 genome AF: 0.000184 AC: 20 AN: 108750 Hom.: 0 Cov.: 21 AF XY: 0.000193 AC XY: 6 AN XY: 31086

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000285

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000472 Hom.: 4

Bravo AF: 0.000102

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 07, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2018	- -

Dilated cardiomyopathy 3B Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 07, 2016

p.Asn2507Asn in exon 51 of DMD: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 27/47762 European chromosomes, including 8 hemizygotes, by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs112516305). -

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

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 18, 2017

- -

DMD-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 04, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2016

This alteration is classified as likely 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. -

Duchenne muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	0.31
Dann	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs112516305; hg19: chrX-31792098; COSMIC: COSV58892487;