rs61733589

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004006.3(DMD):c.1028G>A(p.Arg343His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,209,847 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 41 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R343S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., 19 hem., cov: 23)

Exomes 𝑓: 0.000061 ( 0 hom. 22 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.618

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=0.013598591).

BP6

Variant X-32645085-C-T is Benign according to our data. Variant chrX-32645085-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 201728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000545 (61/111851) while in subpopulation AFR AF= 0.00178 (55/30851). AF 95% confidence interval is 0.00141. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd at 19 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.1028G>A	p.Arg343His	missense_variant	10/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.1028G>A	p.Arg343His	missense_variant	10/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes

AF:

0.000555

AC:

AN:

111800

Hom.:

Cov.:

AF XY:

0.000559

AC XY:

AN XY:

33976

show subpopulations

Gnomad AFR

AF:

0.00182

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000382

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:

0.0000188

Gnomad OTH

AF:

0.000664

GnomAD3 exomes

AF:

0.000158

AC:

AN:

183378

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

67846

show subpopulations

Gnomad AFR exome

AF:

0.00190

Gnomad AMR exome

AF:

0.0000729

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:

0.0000122

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000610

AC:

AN:

1097996

Hom.:

Cov.:

AF XY:

0.0000605

AC XY:

AN XY:

363398

show subpopulations

Gnomad4 AFR exome

AF:

0.00159

Gnomad4 AMR exome

AF:

0.0000852

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000190

Gnomad4 OTH exome

AF:

0.000108

GnomAD4 genome

AF:

0.000545

AC:

AN:

111851

Hom.:

Cov.:

AF XY:

0.000558

AC XY:

AN XY:

34037

show subpopulations

Gnomad4 AFR

AF:

0.00178

Gnomad4 AMR

AF:

0.000382

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.000656

Alfa

AF:

0.0000855

Hom.:

Bravo

AF:

0.000820

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000124

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 06, 2018	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 18, 2016

- -

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

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 11, 2020

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 21, 2021

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2017

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

0.065

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.91

Cadd

Benign

Dann

Uncertain

0.99

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.65

T;.;T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.014

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.30

Sift4G

Uncertain

0.017

D;D;D;D;T

Polyphen

0.16, 0.11

.;B;.;.;B

Vest4

0.12

MVP

0.47

MPC

0.016

ClinPred

0.013

GERP RS

1.6

gMVP

0.16

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