rs1801187

chrX-32362879-C-T

Variant summary

Our verdict is Benign. Variant got -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 same amino acid change has been previously reported as Likely benignin 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:16
• Conservation: PhyloP100: 4.17

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 -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	UniProt
DMD	NM_004006.3	c.5234G>A	p.Arg1745His	missense_variant	37/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.5234G>A	p.Arg1745His	missense_variant	37/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.385 AC: 42289 AN: 109787 Hom.: 7190 Cov.: 22 AF XY: 0.395 AC XY: 12670 AN XY: 32067

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

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

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.: 22 AF XY: 0.394 AC XY: 12673 AN XY: 32130

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:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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.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	PreventionGenetics, part of Exact Sciences	-	- -
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, 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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Duchenne muscular dystrophy Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	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	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
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

- -

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	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	23
Dann	Pathogenic	1.0
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
MutationTaster	Benign	0.0045	P;P
PrimateAI	Uncertain	0.49	T
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

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