rs3827462

Positions:

chrX-32463465-T-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.3406A>T(p.Thr1136Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00612 in 1,206,084 control chromosomes in the GnomAD database, including 147 homozygotes. There are 3,123 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 benignin UniProt.

Frequency

Genomes: 𝑓 0.0050 ( 6 hom., 255 hem., cov: 23)

Exomes 𝑓: 0.0062 ( 141 hom. 2868 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.140

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=0.003510654).

BP6

Variant X-32463465-T-A is Benign according to our data. Variant chrX-32463465-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 94587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32463465-T-A is described in Lovd as [Likely_benign]. Variant chrX-32463465-T-A is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.3406A>T	p.Thr1136Ser	missense_variant	25/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.3406A>T	p.Thr1136Ser	missense_variant	25/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes

AF:

0.00502

AC:

559

AN:

111447

Hom.:

Cov.:

AF XY:

0.00755

AC XY:

254

AN XY:

33637

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000191

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0356

Gnomad SAS

AF:

0.0472

Gnomad FIN

AF:

0.0441

Gnomad MID

AF:

0.00420

Gnomad NFE

AF:

0.000715

Gnomad OTH

AF:

0.00265

GnomAD3 exomes

AF:

0.0116

AC:

2044

AN:

175573

Hom.:

AF XY:

0.0144

AC XY:

877

AN XY:

60789

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000751

Gnomad ASJ exome

AF:

0.00150

Gnomad EAS exome

AF:

0.0332

Gnomad SAS exome

AF:

0.0499

Gnomad FIN exome

AF:

0.0395

Gnomad NFE exome

AF:

0.000885

Gnomad OTH exome

AF:

0.00644

GnomAD4 exome

AF:

0.00623

AC:

6823

AN:

1094585

Hom.:

141

Cov.:

AF XY:

0.00796

AC XY:

2868

AN XY:

360407

show subpopulations

Gnomad4 AFR exome

AF:

0.000190

Gnomad4 AMR exome

AF:

0.0000572

Gnomad4 ASJ exome

AF:

0.000777

Gnomad4 EAS exome

AF:

0.0698

Gnomad4 SAS exome

AF:

0.0508

Gnomad4 FIN exome

AF:

0.0387

Gnomad4 NFE exome

AF:

0.000227

Gnomad4 OTH exome

AF:

0.00522

GnomAD4 genome

AF:

0.00503

AC:

561

AN:

111499

Hom.:

Cov.:

AF XY:

0.00757

AC XY:

255

AN XY:

33699

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000191

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0360

Gnomad4 SAS

AF:

0.0477

Gnomad4 FIN

AF:

0.0441

Gnomad4 NFE

AF:

0.000715

Gnomad4 OTH

AF:

0.00262

Alfa

AF:

0.00269

Hom.:

Bravo

AF:

0.00162

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000892

AC:

ExAC

AF:

0.0130

AC:

1577

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 04, 2015	p.Thr1136Ser in exon 25 of DMD: This variant is not expected to have clinical si gnificance because it has been identified in 7% (451/6490) of South Asian chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs3827462). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 07, 2021	Variant summary: DMD c.3406A>T (p.Thr1136Ser) results in a conservative amino acid change located in the Central rod domain (Repeat 7) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.012 in 175573 control chromosomes, predominantly at a frequency of 0.05 within the South Asian subpopulation in the gnomAD database, including 18 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 4533 fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophinopathies phenotype (1.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as benign (n=4) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 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. -

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 10, 2019

- -

Primary dilated cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Mar 11, 2015

- -

Duchenne muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2016

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

-0.82

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.24

DANN

Benign

0.45

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.19

T;.;T;T

MetaRNN

Benign

0.0035

T;T;T;T

MetaSVM

Benign

-0.94

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.28

Sift4G

Benign

0.93

T;T;T;T

Polyphen

0.0010

.;B;.;.

Vest4

0.046

MutPred

0.31

.;.;Gain of disorder (P = 0.0598);Gain of disorder (P = 0.0598);

MPC

0.016

ClinPred

0.0099

GERP RS

-0.42

gMVP

0.057

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