rs145739725

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_004006.3(DMD):c.1687C>T(p.Arg563Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000081 in 1,209,239 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 35 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R563H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000078 ( 0 hom. 32 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 4.34

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.287921).

BP6

Variant X-32573762-G-A is Benign according to our data. Variant chrX-32573762-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289591.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=3}. Variant chrX-32573762-G-A is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.1687C>T	p.Arg563Cys	missense_variant	14/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.1687C>T	p.Arg563Cys	missense_variant	14/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes

AF:

0.000107

AC:

AN:

111844

Hom.:

Cov.:

AF XY:

0.0000881

AC XY:

AN XY:

34060

show subpopulations

Gnomad AFR

AF:

0.0000976

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000952

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:

0.000150

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000548

AC:

AN:

182567

Hom.:

AF XY:

0.0000298

AC XY:

AN XY:

67189

show subpopulations

Gnomad AFR exome

AF:

0.0000762

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000111

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000784

AC:

AN:

1097395

Hom.:

Cov.:

AF XY:

0.0000882

AC XY:

AN XY:

362827

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000915

Gnomad4 OTH exome

AF:

0.000109

GnomAD4 genome

AF:

0.000107

AC:

AN:

111844

Hom.:

Cov.:

AF XY:

0.0000881

AC XY:

AN XY:

34060

show subpopulations

Gnomad4 AFR

AF:

0.0000976

Gnomad4 AMR

AF:

0.0000952

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000150

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000324

Hom.:

Bravo

AF:

0.0000945

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 30, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2019	- -

Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Duchenne muscular dystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2020

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.28

Cadd

Uncertain

Dann

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

D;.;D;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.29

T;T;T;T;T;T

MetaSVM

Benign

-0.55

MutationTaster

Benign

0.96

D;N;N

PrimateAI

Benign

0.29

Sift4G

Uncertain

0.0090

D;D;D;D;D;D

Polyphen

0.95, 0.99

.;P;.;.;D;.

Vest4

0.37

MVP

0.65

MPC

0.022

ClinPred

0.30

GERP RS

4.1

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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