NM_004006.3:c.1252A>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004006.3(DMD):c.1252A>T(p.Thr418Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000431 in 1,208,414 control chromosomes in the GnomAD database, including 1 homozygotes. There are 159 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., 9 hem., cov: 23)

Exomes 𝑓: 0.00045 ( 1 hom. 150 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.922

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.043501675).

BP6

Variant X-32644211-T-A is Benign according to our data. Variant chrX-32644211-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 166863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32644211-T-A is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.1252A>T	p.Thr418Ser	missense_variant	Exon 11 of 79	ENST00000357033.9	NP_003997.2	P11532

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9 link	c.1252A>T	p.Thr418Ser	missense_variant	Exon 11 of 79	1	NM_004006.3	ENSP00000354923.3		A0A075B6G3

Frequencies

GnomAD3 genomes

AF:

0.000251

AC:

AN:

111733

Hom.:

Cov.:

AF XY:

0.000265

AC XY:

AN XY:

33927

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000191

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000471

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000235

AC:

AN:

183104

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

67616

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000188

Gnomad NFE exome

AF:

0.000428

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000450

AC:

493

AN:

1096681

Hom.:

Cov.:

AF XY:

0.000414

AC XY:

150

AN XY:

362107

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000297

Gnomad4 NFE exome

AF:

0.000546

Gnomad4 OTH exome

AF:

0.000434

GnomAD4 genome

AF:

0.000251

AC:

AN:

111733

Hom.:

Cov.:

AF XY:

0.000265

AC XY:

AN XY:

33927

show subpopulations

Gnomad4 AFR

AF:

0.0000325

Gnomad4 AMR

AF:

0.000191

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000471

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000463

Hom.:

Bravo

AF:

0.000253

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.000206

AC:

EpiCase

AF:

0.000765

EpiControl

AF:

0.000653

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DMD: BP4, BS1 -

Jun 15, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 02, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Mar 05, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 18, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Thr418Ser in exon 11 of DMD: This variant is not expected to have clinical sig nificance because it was seen in 20/47913 European chromosomes, including 5 hem izygotes, by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs201341211) and due to a lack of conservation across species, includ ing mammals. Of note, >5 mammals (Ferret, Panda, Pacific Walrus, Weddell seal, M anatee, Armadillo, Platypus) have serine (Ser) at this position despite high nea rby amino acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. -

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

Benign:1

Jun 24, 2019

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Feb 13, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.95

CADD

Benign

8.6

DANN

Benign

0.69

DEOGEN2

Benign

0.20

.;T;.;.;T

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.48

T;.;T;T;T

M_CAP

Benign

0.0054

MetaRNN

Benign

0.044

T;T;T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.30

PROVEAN

Benign

0.51

.;N;.;N;N

REVEL

Benign

0.023

Sift

Benign

0.87

.;T;.;T;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0

.;B;.;.;B

Vest4

0.24

MutPred

0.30

.;.;Gain of phosphorylation at T418 (P = 0.0675);Gain of phosphorylation at T418 (P = 0.0675);.;

MVP

0.27

MPC

0.015

ClinPred

0.011

GERP RS

3.3

gMVP

0.068

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