rs1800278

Positions:

chrX-31478309-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004006.3(DMD):c.8734A>G(p.Asn2912Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,209,467 control chromosomes in the GnomAD database, including 198 homozygotes. There are 5,390 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.029 ( 85 hom., 880 hem., cov: 23)

Exomes 𝑓: 0.013 ( 113 hom. 4510 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:17

Conservation

PhyloP100: 0.521

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=0.0015425086).

BP6

Variant X-31478309-T-C is Benign according to our data. Variant chrX-31478309-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 11268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-31478309-T-C is described in Lovd as [Benign]. Variant chrX-31478309-T-C is described in Lovd as [Likely_benign]. Variant chrX-31478309-T-C is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.8734A>G	p.Asn2912Asp	missense_variant	59/79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.8734A>G	p.Asn2912Asp	missense_variant	59/79	1	NM_004006.3	ENSP00000354923	P4

Frequencies

GnomAD3 genomes

AF:

0.0286

AC:

3178

AN:

111262

Hom.:

Cov.:

AF XY:

0.0262

AC XY:

875

AN XY:

33438

show subpopulations

Gnomad AFR

AF:

0.0700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0172

Gnomad ASJ

AF:

0.0185

Gnomad EAS

AF:

0.0434

Gnomad SAS

AF:

0.00842

Gnomad FIN

AF:

0.0149

Gnomad MID

AF:

0.0210

Gnomad NFE

AF:

0.00956

Gnomad OTH

AF:

0.0234

GnomAD3 exomes

AF:

0.0213

AC:

3896

AN:

183245

Hom.:

AF XY:

0.0179

AC XY:

1214

AN XY:

67719

show subpopulations

Gnomad AFR exome

AF:

0.0767

Gnomad AMR exome

AF:

0.0246

Gnomad ASJ exome

AF:

0.0168

Gnomad EAS exome

AF:

0.0458

Gnomad SAS exome

AF:

0.0125

Gnomad FIN exome

AF:

0.0194

Gnomad NFE exome

AF:

0.0102

Gnomad OTH exome

AF:

0.0157

GnomAD4 exome

AF:

0.0133

AC:

14646

AN:

1098149

Hom.:

113

Cov.:

AF XY:

0.0124

AC XY:

4510

AN XY:

363505

show subpopulations

Gnomad4 AFR exome

AF:

0.0722

Gnomad4 AMR exome

AF:

0.0245

Gnomad4 ASJ exome

AF:

0.0177

Gnomad4 EAS exome

AF:

0.0422

Gnomad4 SAS exome

AF:

0.0118

Gnomad4 FIN exome

AF:

0.0186

Gnomad4 NFE exome

AF:

0.00951

Gnomad4 OTH exome

AF:

0.0176

GnomAD4 genome

AF:

0.0286

AC:

3183

AN:

111318

Hom.:

Cov.:

AF XY:

0.0263

AC XY:

880

AN XY:

33504

show subpopulations

Gnomad4 AFR

AF:

0.0700

Gnomad4 AMR

AF:

0.0173

Gnomad4 ASJ

AF:

0.0185

Gnomad4 EAS

AF:

0.0433

Gnomad4 SAS

AF:

0.00845

Gnomad4 FIN

AF:

0.0149

Gnomad4 NFE

AF:

0.00956

Gnomad4 OTH

AF:

0.0225

Alfa

AF:

0.0151

Hom.:

857

Bravo

AF:

0.0327

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.00831

AC:

ESP6500AA

AF:

0.0720

AC:

276

ESP6500EA

AF:

0.00847

AC:

ExAC

AF:

0.0211

AC:

2561

EpiCase

AF:

0.00840

EpiControl

AF:

0.00741

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2015	p.Asn2912Asp in exon 59 of DMD: This variant is not expected to have clinical si gnificance because it has been identified in 7.6% (802/10506) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs1800278). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2019	Variant summary: DMD c.8734A>G (p.Asn2912Asp) results in a conservative amino acid change located in in a spectrin/alpha-actinin repeat (IPR018159) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.022 in 200085 control chromosomes in the gnomAD database, including 59 homozygotes and 1416 hemizygotes. The observed variant frequency is significantly higher than expected for a pathogenic variant in DMD causing Dystrophinopathies phenotype, strongly suggesting that the variant is benign. Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign (6x) and once as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 08, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Duchenne muscular dystrophy

Uncertain:1Benign:3

Uncertain significance, no assertion criteria provided	literature only	OMIM	Sep 01, 1994	- -
Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 11, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 02, 2019

- -

Dilated cardiomyopathy 3B

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 23, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.76

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.29

.;T;T;T;.;.;T;.;.;T

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.61

T;.;.;.;.;T;.;T;T;.

MetaRNN

Benign

0.0015

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

P;P;P;P;P;P;P

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.4

N;.;N;N;N;.;N;.;N;N

REVEL

Benign

0.062

Sift

Benign

0.17

T;.;D;T;D;.;T;.;T;D

Sift4G

Benign

0.19

T;T;T;T;T;T;T;T;T;T

Polyphen

0.019, 0.26, 0.0070, 0.0

.;.;B;B;B;.;B;.;.;B

Vest4

0.12, 0.12, 0.092, 0.072, 0.088, 0.087, 0.073, 0.053, 0.10

MPC

0.044

ClinPred

0.018

GERP RS

1.7

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