rs1800273

chrX-31968490-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 10/16 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 3.53

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=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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 40 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	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	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.: 40 Cov.: 23 AF XY: 0.0251 AC XY: 851 AN XY: 33888

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.: 64 AF XY: 0.0266 AC XY: 1787 AN XY: 67147

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.: 31 AF XY: 0.0366 AC XY: 13292 AN XY: 362857

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.: 40 Cov.: 23 AF XY: 0.0251 AC XY: 851 AN XY: 33949

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: 27

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:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 10, 2014	- -
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, 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	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

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	- -

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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.
FATHMM_MKL	Uncertain	0.88	D
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.97	P;P;P;P;P;P;P
PrimateAI	Benign	0.33	T
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	T
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

Other links and lift over

dbSNP: rs1800273; hg19: chrX-31986607; COSMIC: COSV58925650;