rs1801187

Variant names:

• chrX-32362879-C-T
• rs1801187
• NM_004006.3:c.5234G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1745C) has been classified as Uncertain significance.

• 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 4.17
• Publications: 48 publications found

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 Gene-Disease associations (from GenCC):

• Becker muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• dilated cardiomyopathy 3B

  Inheritance: XL Classification: DEFINITIVE Submitted by: Ambry Genetics
• Duchenne and Becker muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• Duchenne muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• progressive muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 94657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.5234G>A	p.Arg1745His	missense_variant	Exon 37 of 79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.5234G>A	p.Arg1745His	missense_variant	Exon 37 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes AF: 0.385 AC: 42289 AN: 109787 Hom.: 7190 Cov.: 22

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

GnomAD2 exomes AF: 0.528 AC: 96466 AN: 182810 AF XY: 0.533

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 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.: 34 AF XY: 0.494 AC XY: 179548 AN XY: 363113

African (AFR) AF: 0.0666 AC: 1758 AN: 26390

American (AMR) AF: 0.711 AC: 25021 AN: 35186

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 8686 AN: 19383

East Asian (EAS) AF: 0.685 AC: 20687 AN: 30197

South Asian (SAS) AF: 0.662 AC: 35836 AN: 54144

European-Finnish (FIN) AF: 0.522 AC: 21154 AN: 40503

Middle Eastern (MID) AF: 0.488 AC: 2017 AN: 4133

European-Non Finnish (NFE) AF: 0.471 AC: 396310 AN: 841668

Other (OTH) AF: 0.474 AC: 21844 AN: 46077

GnomAD4 genome AF: 0.385 AC: 42276 AN: 109840 Hom.: 7187 Cov.: 22 AF XY: 0.394 AC XY: 12673 AN XY: 32130

African (AFR) AF: 0.0830 AC: 2522 AN: 30397

American (AMR) AF: 0.581 AC: 5909 AN: 10172

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1123 AN: 2614

East Asian (EAS) AF: 0.711 AC: 2437 AN: 3427

South Asian (SAS) AF: 0.655 AC: 1691 AN: 2581

European-Finnish (FIN) AF: 0.513 AC: 2890 AN: 5629

Middle Eastern (MID) AF: 0.395 AC: 85 AN: 215

European-Non Finnish (NFE) AF: 0.470 AC: 24713 AN: 52634

Other (OTH) AF: 0.415 AC: 622 AN: 1497

Alfa AF: 0.445 Hom.: 64748

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:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 18, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 20, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 11, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 29, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

not provided Benign:3

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 28, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Duchenne muscular dystrophy Benign:3

Aug 01, 2017

Phosphorus, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 3B Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Apr 20, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Mar 11, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	.;T;.;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D;.;D;D
MetaRNN	Benign	0.000012	T;T;T;T
MetaSVM	Benign	-0.90	T
PhyloP100		4.2
PrimateAI	Uncertain	0.49	T
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	T
GERP RS		5.2
gMVP		0.37
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1801187; hg19: chrX-32380996; COSMIC: COSV63739824; COSMIC: COSV63739824;