rs147822019

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PS1_ModerateBP6BS2

The NM_004006.3(DMD):c.1934A>G(p.Asp645Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000216 in 1,210,165 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 81 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., 10 hem., cov: 23)

Exomes 𝑓: 0.00020 ( 0 hom. 71 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 7.19

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 -3 ACMG points.

PS1

Transcript NM_004006.3 (DMD) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

BP6

Variant X-32565760-T-C is Benign according to our data. Variant chrX-32565760-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281435.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3, Likely_benign=5}. Variant chrX-32565760-T-C is described in Lovd as [Pathogenic]. Variant chrX-32565760-T-C is described in Lovd as [Benign]. Variant chrX-32565760-T-C is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.1934A>G	p.Asp645Gly	missense_variant	16/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.1934A>G	p.Asp645Gly	missense_variant	16/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

112058

Hom.:

Cov.:

AF XY:

0.000292

AC XY:

AN XY:

34220

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000822

Gnomad MID

AF:

0.00417

Gnomad NFE

AF:

0.000601

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000273

AC:

AN:

183196

Hom.:

AF XY:

0.000251

AC XY:

AN XY:

67754

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00100

Gnomad NFE exome

AF:

0.000367

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000203

AC:

223

AN:

1098053

Hom.:

Cov.:

AF XY:

0.000195

AC XY:

AN XY:

363437

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.000199

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.000740

Gnomad4 NFE exome

AF:

0.000198

Gnomad4 OTH exome

AF:

0.000347

GnomAD4 genome

AF:

0.000348

AC:

AN:

112112

Hom.:

Cov.:

AF XY:

0.000292

AC XY:

AN XY:

34284

show subpopulations

Gnomad4 AFR

AF:

0.0000324

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000822

Gnomad4 NFE

AF:

0.000601

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000365

Hom.:

Bravo

AF:

0.000257

ExAC

AF:

0.000305

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2020	This variant is associated with the following publications: (PMID: 7981690, 24274981, 25220406) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 10, 2017	- -

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 29, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	Variant summary: DMD c.1934A>G (p.Asp645Gly) results in a non-conservative amino acid change located in the Rod domain (Prior_1994) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 183396 control chromosomes. The observed variant frequency is approximately 24.72 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 benign. c.1934A>G has been reported in the literature in individuals affected with DMD (Prior_1994). This report does not provide unequivocal conclusions about association of the variant with Dystrophinopathies. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Six submitters classified as likely benign/benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jan 27, 2017	- -

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

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 22, 2020

- -

DMD-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 24, 2022

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.17

Cadd

Uncertain

Dann

Uncertain

1.0

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.73

T;.;T;T;T

M_CAP

Benign

0.050

MetaRNN

Benign

0.22

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.70

D;D;D

PrimateAI

Benign

0.25

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

0.048, 0.46

.;B;.;.;P

Vest4

0.47

MVP

0.76

MPC

0.017

ClinPred

0.12

GERP RS

5.3

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.34

Position offset: 1

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