rs1801187

Positions:

chrX-32362879-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004006.3(DMD):c.5234G>A(p.Arg1745His) variant causes a missense change. The variant allele was found at a frequency of 0.477 in 1,207,521 control chromosomes in the GnomAD database, including 96,016 homozygotes. There are 192,221 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.38 ( 7187 hom., 12673 hem., cov: 22)

Exomes 𝑓: 0.49 ( 88829 hom. 179548 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 4.17

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 (MetaRNN=1.1590453E-5).

BP6

Variant X-32362879-C-T is Benign according to our data. Variant chrX-32362879-C-T is described in ClinVar as [Benign]. Clinvar id is 94657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32362879-C-T is described in Lovd as [Benign]. Variant chrX-32362879-C-T is described in Lovd as [Pathogenic]. Variant chrX-32362879-C-T is described in Lovd as [Likely_pathogenic]. Variant chrX-32362879-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.688 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.5234G>A	p.Arg1745His	missense_variant	37/79	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.5234G>A	p.Arg1745His	missense_variant	37/79	1	NM_004006.3	ENSP00000354923.3		A0A075B6G3

Frequencies

GnomAD3 genomes

AF:

0.385

AC:

42289

AN:

109787

Hom.:

7190

Cov.:

AF XY:

0.395

AC XY:

12670

AN XY:

32067

show subpopulations

Gnomad AFR

AF:

0.0832

Gnomad AMI

AF:

0.421

Gnomad AMR

AF:

0.580

Gnomad ASJ

AF:

0.430

Gnomad EAS

AF:

0.710

Gnomad SAS

AF:

0.658

Gnomad FIN

AF:

0.513

Gnomad MID

AF:

0.396

Gnomad NFE

AF:

0.470

Gnomad OTH

AF:

0.419

GnomAD3 exomes

AF:

0.528

AC:

96466

AN:

182810

Hom.:

17898

AF XY:

0.533

AC XY:

35913

AN XY:

67334

show subpopulations

Gnomad AFR exome

AF:

0.0726

Gnomad AMR exome

AF:

0.728

Gnomad ASJ exome

AF:

0.443

Gnomad EAS exome

AF:

0.735

Gnomad SAS exome

AF:

0.660

Gnomad FIN exome

AF:

0.529

Gnomad NFE exome

AF:

0.477

Gnomad OTH exome

AF:

0.506

GnomAD4 exome

AF:

0.486

AC:

533313

AN:

1097681

Hom.:

88829

Cov.:

AF XY:

0.494

AC XY:

179548

AN XY:

363113

show subpopulations

Gnomad4 AFR exome

AF:

0.0666

Gnomad4 AMR exome

AF:

0.711

Gnomad4 ASJ exome

AF:

0.448

Gnomad4 EAS exome

AF:

0.685

Gnomad4 SAS exome

AF:

0.662

Gnomad4 FIN exome

AF:

0.522

Gnomad4 NFE exome

AF:

0.471

Gnomad4 OTH exome

AF:

0.474

GnomAD4 genome

AF:

0.385

AC:

42276

AN:

109840

Hom.:

7187

Cov.:

AF XY:

0.394

AC XY:

12673

AN XY:

32130

show subpopulations

Gnomad4 AFR

AF:

0.0830

Gnomad4 AMR

AF:

0.581

Gnomad4 ASJ

AF:

0.430

Gnomad4 EAS

AF:

0.711

Gnomad4 SAS

AF:

0.655

Gnomad4 FIN

AF:

0.513

Gnomad4 NFE

AF:

0.470

Gnomad4 OTH

AF:

0.415

Alfa

AF:

0.467

Hom.:

53098

Bravo

AF:

0.381

TwinsUK

AF:

0.479

AC:

1775

ALSPAC

AF:

0.472

AC:

1363

ESP6500AA

AF:

0.0806

AC:

309

ESP6500EA

AF:

0.477

AC:

3209

ExAC

AF:

0.516

AC:

62654

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 29, 2014	p.Arg1745His in exon 37 of DMD: This variant is not expected to have clinical si gnificance because it has been identified in 48% (3209/6728) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs1801187). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2019	Variant summary: DMD c.5234G>A (p.Arg1745His) results in a non-conservative amino acid change located in a spectrin repeat (IPR018159) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.51 in 199355 control chromosomes, suggesting that it is the major allele and therefore benign. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign (5x) and once as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Duchenne muscular dystrophy

Benign:3

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

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

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 20, 2017

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 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

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

.;T;.;.

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

D;.;D;D

MetaRNN

Benign

0.000012

T;T;T;T

MetaSVM

Benign

-0.90

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.4

.;N;.;N

REVEL

Uncertain

0.31

Sift

Uncertain

0.0060

.;D;.;D

Sift4G

Uncertain

0.020

D;D;D;D

Polyphen

1.0

.;D;.;.

Vest4

0.15

MPC

0.071

ClinPred

0.020

GERP RS

5.2

gMVP

0.37

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

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