rs1800269

Positions:

chrX-32448508-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004006.3(DMD):c.3734C>T(p.Thr1245Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0116 in 1,206,985 control chromosomes in the GnomAD database, including 169 homozygotes. There are 4,240 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 UniProt.

Frequency

Genomes: 𝑓 0.0099 ( 14 hom., 315 hem., cov: 23)

Exomes 𝑓: 0.012 ( 155 hom. 3925 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 6.09

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=0.0023860931).

BP6

Variant X-32448508-G-A is Benign according to our data. Variant chrX-32448508-G-A is described in ClinVar as [Benign]. Clinvar id is 94604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32448508-G-A is described in Lovd as [Benign]. Variant chrX-32448508-G-A is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0798 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.3734C>T	p.Thr1245Ile	missense_variant	27/79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.3734C>T	p.Thr1245Ile	missense_variant	27/79	1	NM_004006.3	ENSP00000354923	P4

Frequencies

GnomAD3 genomes

AF:

0.00995

AC:

1105

AN:

111014

Hom.:

Cov.:

AF XY:

0.00937

AC XY:

315

AN XY:

33632

show subpopulations

Gnomad AFR

AF:

0.00212

Gnomad AMI

AF:

0.00872

Gnomad AMR

AF:

0.0401

Gnomad ASJ

AF:

0.0103

Gnomad EAS

AF:

0.000285

Gnomad SAS

AF:

0.00184

Gnomad FIN

AF:

0.00295

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0104

Gnomad OTH

AF:

0.0149

GnomAD3 exomes

AF:

0.0189

AC:

3452

AN:

182401

Hom.:

112

AF XY:

0.0144

AC XY:

971

AN XY:

67275

show subpopulations

Gnomad AFR exome

AF:

0.00199

Gnomad AMR exome

AF:

0.0894

Gnomad ASJ exome

AF:

0.00820

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.00226

Gnomad FIN exome

AF:

0.00438

Gnomad NFE exome

AF:

0.00919

Gnomad OTH exome

AF:

0.0127

GnomAD4 exome

AF:

0.0118

AC:

12882

AN:

1095919

Hom.:

155

Cov.:

AF XY:

0.0108

AC XY:

3925

AN XY:

362543

show subpopulations

Gnomad4 AFR exome

AF:

0.00153

Gnomad4 AMR exome

AF:

0.0823

Gnomad4 ASJ exome

AF:

0.00877

Gnomad4 EAS exome

AF:

0.0000664

Gnomad4 SAS exome

AF:

0.00288

Gnomad4 FIN exome

AF:

0.00370

Gnomad4 NFE exome

AF:

0.0107

Gnomad4 OTH exome

AF:

0.00953

GnomAD4 genome

AF:

0.00995

AC:

1105

AN:

111066

Hom.:

Cov.:

AF XY:

0.00935

AC XY:

315

AN XY:

33694

show subpopulations

Gnomad4 AFR

AF:

0.00211

Gnomad4 AMR

AF:

0.0400

Gnomad4 ASJ

AF:

0.0103

Gnomad4 EAS

AF:

0.000286

Gnomad4 SAS

AF:

0.00184

Gnomad4 FIN

AF:

0.00295

Gnomad4 NFE

AF:

0.0104

Gnomad4 OTH

AF:

0.0147

Alfa

AF:

0.00978

Hom.:

410

Bravo

AF:

0.0143

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.0135

AC:

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.0109

AC:

ExAC

AF:

0.0139

AC:

1686

EpiCase

AF:

0.0104

EpiControl

AF:

0.00845

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Jan 13, 2015	p.Thr1245Ile in exon 27 of DMD: This variant is not expected to have clinical si gnificance because it has been identified in 1.1% (73/6728) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS/; dbSNP rs1800269). -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 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	Eurofins Ntd Llc (ga)	Aug 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 12, 2020	Variant summary: DMD c.3734C>T (p.Thr1245Ile) 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 0.019 in 182401 control chromosomes, predominantly at a frequency of 0.089 within the Latino subpopulation in the gnomAD database, including 112 homozygotes and 971 hemizygotes. The observed variant frequency within Latino control individuals in the gnomAD database is significantly higher than expected for a pathogenic variant in DMD causing Dystrophinopathies phenotype, strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. Six ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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 19, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 21, 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. -

Duchenne muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 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

0.16

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

.;T;.;.

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.89

D;.;D;D

MetaRNN

Benign

0.0024

T;T;T;T

MetaSVM

Benign

-0.96

MutationTaster

Benign

0.89

P;P

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.7

.;N;.;N

REVEL

Benign

0.12

Sift

Benign

0.044

.;D;.;D

Sift4G

Uncertain

0.049

D;D;D;D

Polyphen

0.83

.;P;.;.

Vest4

0.31

MPC

0.019

ClinPred

0.036

GERP RS

3.1

gMVP

0.15

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