rs1800273

Positions:

chrX-31968490-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004006.3(DMD):c.6463C>T(p.Arg2155Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0367 in 1,208,510 control chromosomes in the GnomAD database, including 655 homozygotes. There are 14,143 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/17 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 benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2155Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.027 ( 40 hom., 851 hem., cov: 23)

Exomes 𝑓: 0.038 ( 615 hom. 13292 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.53

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004711747).

BP6

Variant X-31968490-G-A is Benign according to our data. Variant chrX-31968490-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 94741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-31968490-G-A is described in Lovd as [Benign]. Variant chrX-31968490-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.027 (3018/111649) while in subpopulation NFE AF= 0.0415 (2198/53004). AF 95% confidence interval is 0.04. There are 40 homozygotes in gnomad4. There are 851 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 40 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.6463C>T	p.Arg2155Trp	missense_variant	45/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.6463C>T	p.Arg2155Trp	missense_variant	45/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes

AF:

0.0271

AC:

3020

AN:

111598

Hom.:

Cov.:

AF XY:

0.0251

AC XY:

851

AN XY:

33888

show subpopulations

Gnomad AFR

AF:

0.00573

Gnomad AMI

AF:

0.0117

Gnomad AMR

AF:

0.0322

Gnomad ASJ

AF:

0.0182

Gnomad EAS

AF:

0.000846

Gnomad SAS

AF:

0.00592

Gnomad FIN

AF:

0.0297

Gnomad MID

AF:

0.0212

Gnomad NFE

AF:

0.0415

Gnomad OTH

AF:

0.0315

GnomAD3 exomes

AF:

0.0261

AC:

4756

AN:

182171

Hom.:

AF XY:

0.0266

AC XY:

1787

AN XY:

67147

show subpopulations

Gnomad AFR exome

AF:

0.00579

Gnomad AMR exome

AF:

0.0183

Gnomad ASJ exome

AF:

0.0199

Gnomad EAS exome

AF:

0.0000725

Gnomad SAS exome

AF:

0.00498

Gnomad FIN exome

AF:

0.0325

Gnomad NFE exome

AF:

0.0407

Gnomad OTH exome

AF:

0.0274

GnomAD4 exome

AF:

0.0377

AC:

41356

AN:

1096861

Hom.:

615

Cov.:

AF XY:

0.0366

AC XY:

13292

AN XY:

362857

show subpopulations

Gnomad4 AFR exome

AF:

0.00410

Gnomad4 AMR exome

AF:

0.0188

Gnomad4 ASJ exome

AF:

0.0182

Gnomad4 EAS exome

AF:

0.0000332

Gnomad4 SAS exome

AF:

0.00521

Gnomad4 FIN exome

AF:

0.0321

Gnomad4 NFE exome

AF:

0.0441

Gnomad4 OTH exome

AF:

0.0329

GnomAD4 genome

AF:

0.0270

AC:

3018

AN:

111649

Hom.:

Cov.:

AF XY:

0.0251

AC XY:

851

AN XY:

33949

show subpopulations

Gnomad4 AFR

AF:

0.00571

Gnomad4 AMR

AF:

0.0321

Gnomad4 ASJ

AF:

0.0182

Gnomad4 EAS

AF:

0.000849

Gnomad4 SAS

AF:

0.00593

Gnomad4 FIN

AF:

0.0297

Gnomad4 NFE

AF:

0.0415

Gnomad4 OTH

AF:

0.0311

Alfa

AF:

0.0367

Hom.:

1962

Bravo

AF:

0.0255

TwinsUK

AF:

0.0407

AC:

151

ALSPAC

AF:

0.0422

AC:

122

ESP6500AA

AF:

0.00704

AC:

ESP6500EA

AF:

0.0378

AC:

254

ExAC

AF:

0.0265

AC:

3209

EpiCase

AF:

0.0419

EpiControl

AF:

0.0445

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 10, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 04, 2019	Variant summary: DMD c.6463C>T (p.Arg2155Trp) results in a non-conservative amino acid change in 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 199100 control chromosomes in the gnomAD database, including 80 homozygotes and 1967 hemizygotes, which is significantly over the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophinopathies phenotype (0.000008824), strongly suggesting that the variant is benign. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 29, 2014	p.Arg2155Trp in exon 45 of DMD: This variant is not expected to have clinical si gnificance because it has been identified in 3.8% (254/6725) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs1800273). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

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	Nov 01, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 31, 2017

- -

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. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 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. -

Duchenne muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.91

.;D

MetaRNN

Benign

0.0047

T;T

MetaSVM

Benign

-0.96

MutationTaster

Benign

0.97

P;P;P;P;P;P;P

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.16

Sift

Benign

0.18

T;T

Sift4G

Uncertain

0.0050

D;D

Polyphen

0.99

D;.

Vest4

0.33

MPC

0.089

ClinPred

0.024

GERP RS

2.5

gMVP

0.25

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