rs72468681

Positions:

chrX-32491508-A-C

Variant summary

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

The ENST00000357033.9(DMD):c.2391T>G(p.Asn797Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,208,031 control chromosomes in the GnomAD database, including 80 homozygotes. There are 4,378 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0070 ( 2 hom., 221 hem., cov: 24)

Exomes 𝑓: 0.012 ( 78 hom. 4157 hem. )

Consequence

DMD
ENST00000357033.9 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: 1.55

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=0.008066297).

BP6

Variant X-32491508-A-C is Benign according to our data. Variant chrX-32491508-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 94510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32491508-A-C is described in Lovd as [Benign]. Variant chrX-32491508-A-C is described in Lovd as [Pathogenic]. Variant chrX-32491508-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00695 (780/112178) while in subpopulation NFE AF= 0.0117 (622/53237). AF 95% confidence interval is 0.0109. There are 2 homozygotes in gnomad4. There are 221 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.2391T>G	p.Asn797Lys	missense_variant	20/79	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.2391T>G	p.Asn797Lys	missense_variant	20/79	1	NM_004006.3	ENSP00000354923	P4

Frequencies

GnomAD3 genomes

AF:

0.00697

AC:

782

AN:

112124

Hom.:

Cov.:

AF XY:

0.00645

AC XY:

221

AN XY:

34270

show subpopulations

Gnomad AFR

AF:

0.00185

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00313

Gnomad ASJ

AF:

0.00113

Gnomad EAS

AF:

0.000277

Gnomad SAS

AF:

0.00221

Gnomad FIN

AF:

0.00721

Gnomad MID

AF:

0.0169

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.00794

GnomAD3 exomes

AF:

0.00649

AC:

1158

AN:

178379

Hom.:

AF XY:

0.00652

AC XY:

412

AN XY:

63219

show subpopulations

Gnomad AFR exome

AF:

0.00201

Gnomad AMR exome

AF:

0.00184

Gnomad ASJ exome

AF:

0.000809

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00404

Gnomad FIN exome

AF:

0.00700

Gnomad NFE exome

AF:

0.0109

Gnomad OTH exome

AF:

0.00698

GnomAD4 exome

AF:

0.0119

AC:

13021

AN:

1095853

Hom.:

Cov.:

AF XY:

0.0115

AC XY:

4157

AN XY:

361375

show subpopulations

Gnomad4 AFR exome

AF:

0.00144

Gnomad4 AMR exome

AF:

0.00222

Gnomad4 ASJ exome

AF:

0.000671

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00351

Gnomad4 FIN exome

AF:

0.00678

Gnomad4 NFE exome

AF:

0.0142

Gnomad4 OTH exome

AF:

0.00974

GnomAD4 genome

AF:

0.00695

AC:

780

AN:

112178

Hom.:

Cov.:

AF XY:

0.00644

AC XY:

221

AN XY:

34334

show subpopulations

Gnomad4 AFR

AF:

0.00185

Gnomad4 AMR

AF:

0.00313

Gnomad4 ASJ

AF:

0.00113

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00221

Gnomad4 FIN

AF:

0.00721

Gnomad4 NFE

AF:

0.0117

Gnomad4 OTH

AF:

0.00784

Alfa

AF:

0.0116

Hom.:

111

Bravo

AF:

0.00620

TwinsUK

AF:

0.0162

AC:

ALSPAC

AF:

0.0135

AC:

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.00832

AC:

ExAC

AF:

0.00675

AC:

819

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 12, 2015	p.Asn797Lys in exon 20 of DMD: This variant is not expected to have clinical sig nificance because it has been identified in 1.2% (432/37288) European (Non-Finni sh) chromosomes by the Exome Aggregation Consortium Sequencing Project (http://e xac.broadinstitute.org/variant/X-32509625-A-C; dbSNP rs72468681). In addition, 5 individuals in this European cohort were homozygous and 141 were hemizygous fo r this variant. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 09, 2020	Variant summary: DMD c.2391T>G (p.Asn797Lys) results in a non-conservative amino acid change located in the Central rod domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0065 in 178379 control chromosomes, predominantly at a frequency of 0.011 within the Non-Finnish European subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 997 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as benign (7x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 24, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 09, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Primary dilated cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Mar 19, 2019	- -
Benign, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Mar 11, 2015	- -

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 20, 2017

- -

Dilated cardiomyopathy 3B

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 24, 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. -

Duchenne muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

.;T;.;.

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.78

T;.;T;T

MetaRNN

Benign

0.0081

T;T;T;T

MetaSVM

Benign

-0.94

MutationTaster

Benign

0.66

D;D

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.77

.;N;.;N

REVEL

Benign

0.081

Sift

Benign

0.81

.;T;.;T

Sift4G

Benign

0.46

T;T;T;T

Polyphen

0.86

.;P;.;.

Vest4

0.34

MutPred

0.40

.;.;Gain of ubiquitination at N797 (P = 0.0138);Gain of ubiquitination at N797 (P = 0.0138);

MVP

0.69

MPC

0.10

ClinPred

0.019

GERP RS

0.18

gMVP

0.078

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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