rs72466590

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004006.3(DMD):c.7183G>A(p.Ala2395Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,209,410 control chromosomes in the GnomAD database, including 4 homozygotes. There are 652 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., 38 hem., cov: 23)

Exomes 𝑓: 0.0018 ( 4 hom. 614 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:14O:1

Conservation

PhyloP100: 1.94

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018843055).

BP6

Variant X-31836735-C-T is Benign according to our data. Variant chrX-31836735-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 94757.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=4, Uncertain_significance=2, not_provided=1}. Variant chrX-31836735-C-T is described in Lovd as [Benign]. Variant chrX-31836735-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00128 (144/112174) while in subpopulation NFE AF= 0.00218 (116/53229). AF 95% confidence interval is 0.00186. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 38 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.7183G>A	p.Ala2395Thr	missense_variant	Exon 49 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.7183G>A	p.Ala2395Thr	missense_variant	Exon 49 of 79	1	NM_004006.3	ENSP00000354923.3		A0A075B6G3

Frequencies

GnomAD3 genomes

AF:

0.00128

AC:

144

AN:

112119

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

34279

show subpopulations

Gnomad AFR

AF:

0.000194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00171

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000370

Gnomad FIN

AF:

0.000164

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00218

Gnomad OTH

AF:

0.00132

GnomAD3 exomes

AF:

0.000867

AC:

159

AN:

183371

Hom.:

AF XY:

0.000825

AC XY:

AN XY:

67841

show subpopulations

Gnomad AFR exome

AF:

0.000228

Gnomad AMR exome

AF:

0.000583

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:

0.00164

Gnomad OTH exome

AF:

0.000663

GnomAD4 exome

AF:

0.00178

AC:

1957

AN:

1097236

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

614

AN XY:

362654

show subpopulations

Gnomad4 AFR exome

AF:

0.000265

Gnomad4 AMR exome

AF:

0.000398

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000663

Gnomad4 SAS exome

AF:

0.0000924

Gnomad4 FIN exome

AF:

0.000272

Gnomad4 NFE exome

AF:

0.00219

Gnomad4 OTH exome

AF:

0.00167

GnomAD4 genome

AF:

0.00128

AC:

144

AN:

112174

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

34344

show subpopulations

Gnomad4 AFR

AF:

0.000194

Gnomad4 AMR

AF:

0.00171

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000371

Gnomad4 FIN

AF:

0.000164

Gnomad4 NFE

AF:

0.00218

Gnomad4 OTH

AF:

0.00130

Alfa

AF:

0.00154

Hom.:

Bravo

AF:

0.00125

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00138

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00223

AC:

ExAC

AF:

0.000733

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:14Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DMD: BP4, BS2 -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 21, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: 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

- -

May 27, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17259292, 23757202, 25447171, 19937601) -

not specified

Uncertain:1Benign:4

Mar 15, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Ala2395Thr va riant in DMD has been reported in 1 child with unexplained sudden death (Campuza no 2014) and 1 mother of a proband with Duchenne Muscular Dystrophy (Taylor 2007 ). It has also been identified in 0.1% (59/47984) of European chromosomes, inclu ding 22 hemizygotes, by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs72466590). Computational prediction tools and conservati on analysis suggest that the p.Ala2395Thr variant may not impact the protein, th ough this information is not predictive enough to rule out pathogenicity. In sum mary, while the clinical significance of the p.Ala2395Thr variant is uncertain, these data suggest that it is more likely to be benign. -

Jun 10, 2019

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 26, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Duchenne muscular dystrophy

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 3B

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiovascular phenotype

Benign:1

Oct 31, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Hereditary skeletal muscle disorder

Benign:1

Apr 17, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B

Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.25

.;.;T;.;.

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.85

T;T;.;T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.019

T;T;T;T;T

MetaSVM

Benign

-0.94

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.88

N;.;N;.;N

REVEL

Benign

0.15

Sift

Benign

0.47

T;.;T;.;T

Sift4G

Benign

0.71

T;T;T;T;T

Polyphen

0.14

.;.;B;.;.

Vest4

0.17, 0.12, 0.22, 0.049

MVP

0.84

MPC

0.016

ClinPred

0.012

GERP RS

4.8

gMVP

0.17

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