rs1800279

Positions:

chrX-31478281-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PS1_ModerateBP4_StrongBP6_Very_StrongBS1BS2

The NM_004006.3(DMD):c.8762A>G(p.His2921Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 1,209,039 control chromosomes in the GnomAD database, including 345 homozygotes. There are 11,312 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Synonymous variant affecting the same amino acid position (i.e. H2921H) has been classified as Benign.

Frequency

Genomes: 𝑓 0.022 ( 24 hom., 722 hem., cov: 22)

Exomes 𝑓: 0.029 ( 321 hom. 10590 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:16

Conservation

PhyloP100: 1.61

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PS1

Transcript NM_004006.3 (DMD) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

BP4

Computational evidence support a benign effect (MetaRNN=0.015792578).

BP6

Variant X-31478281-T-C is Benign according to our data. Variant chrX-31478281-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 11269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-31478281-T-C is described in Lovd as [Benign]. Variant chrX-31478281-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.022 (2442/110875) while in subpopulation NFE AF= 0.032 (1696/52924). AF 95% confidence interval is 0.0308. There are 24 homozygotes in gnomad4. There are 722 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 24 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.8762A>G	p.His2921Arg	missense_variant	59/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.8762A>G	p.His2921Arg	missense_variant	59/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes

AF:

0.0220

AC:

2443

AN:

110823

Hom.:

Cov.:

AF XY:

0.0218

AC XY:

721

AN XY:

33053

show subpopulations

Gnomad AFR

AF:

0.00371

Gnomad AMI

AF:

0.00146

Gnomad AMR

AF:

0.0176

Gnomad ASJ

AF:

0.0190

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0260

Gnomad FIN

AF:

0.0501

Gnomad MID

AF:

0.0254

Gnomad NFE

AF:

0.0320

Gnomad OTH

AF:

0.0223

GnomAD3 exomes

AF:

0.0256

AC:

4685

AN:

183282

Hom.:

AF XY:

0.0262

AC XY:

1773

AN XY:

67748

show subpopulations

Gnomad AFR exome

AF:

0.00365

Gnomad AMR exome

AF:

0.0154

Gnomad ASJ exome

AF:

0.0226

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0283

Gnomad FIN exome

AF:

0.0419

Gnomad NFE exome

AF:

0.0329

Gnomad OTH exome

AF:

0.0325

GnomAD4 exome

AF:

0.0289

AC:

31713

AN:

1098164

Hom.:

321

Cov.:

AF XY:

0.0291

AC XY:

10590

AN XY:

363528

show subpopulations

Gnomad4 AFR exome

AF:

0.00394

Gnomad4 AMR exome

AF:

0.0156

Gnomad4 ASJ exome

AF:

0.0213

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.0317

Gnomad4 FIN exome

AF:

0.0444

Gnomad4 NFE exome

AF:

0.0305

Gnomad4 OTH exome

AF:

0.0273

GnomAD4 genome

AF:

0.0220

AC:

2442

AN:

110875

Hom.:

Cov.:

AF XY:

0.0218

AC XY:

722

AN XY:

33115

show subpopulations

Gnomad4 AFR

AF:

0.00370

Gnomad4 AMR

AF:

0.0175

Gnomad4 ASJ

AF:

0.0190

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0261

Gnomad4 FIN

AF:

0.0501

Gnomad4 NFE

AF:

0.0320

Gnomad4 OTH

AF:

0.0220

Alfa

AF:

0.0306

Hom.:

1311

Bravo

AF:

0.0193

TwinsUK

AF:

0.0318

AC:

118

ALSPAC

AF:

0.0322

AC:

ESP6500AA

AF:

0.00444

AC:

ESP6500EA

AF:

0.0297

AC:

200

ExAC

AF:

0.0269

AC:

3270

EpiCase

AF:

0.0336

EpiControl

AF:

0.0315

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2019	Variant summary: DMD c.8762A>G (p.His2921Arg) 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 0.026 in 200041 control chromosomes in the gnomAD database, including 42 homozygotes and 1923 hemizygotes. These data strongly suggest that the variant is 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	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2014	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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.His2921Arg in exon 59 of DMD: This variant is not expected to have clinical si gnificance because it has been identified in 3% (200/6728) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/; dbSNP rs1800279). -

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -

Duchenne muscular dystrophy

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Becker muscular dystrophy

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Sep 01, 1994

- -

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

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 28, 2017

- -

Dilated cardiomyopathy 3B

Benign:1

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. -

DMD-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2019

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

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 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

0.063

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.70

CADD

Benign

9.5

DANN

Benign

0.70

DEOGEN2

Benign

0.22

.;T;T;T;.;.;T;.;.;T

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.67

T;.;.;.;.;T;.;T;T;.

MetaRNN

Benign

0.016

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationTaster

Benign

0.00034

A;A;A;A;A;A;A

PrimateAI

Benign

0.46

PROVEAN

Benign

0.75

N;.;N;N;N;.;N;.;N;N

REVEL

Benign

0.050

Sift

Benign

1.0

T;.;T;T;T;.;T;.;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T;T;T;T;T

Polyphen

0.0

.;.;B;B;B;.;B;.;.;B

Vest4

0.073, 0.087, 0.089, 0.10, 0.099, 0.093, 0.069

MPC

0.037

ClinPred

0.0018

GERP RS

2.9

gMVP

0.23

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