X-32468688-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_004006.3(DMD):c.2972A>G(p.Glu991Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000827 in 1,209,070 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E991V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000082 ( 0 hom. 1 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.11

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

Becker muscular dystrophy
Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
dilated cardiomyopathy 3B
Inheritance: XL Classification: DEFINITIVE Submitted by: Ambry Genetics
Duchenne and Becker muscular dystrophy
Inheritance: XL Classification: DEFINITIVE Submitted by: Myriad Women’s Health
Duchenne muscular dystrophy
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
progressive muscular dystrophy
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

DMD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BS2

High AC in GnomAdExome4 at 9 XL,AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.2972A>G	p.Glu991Gly	missense_variant	Exon 23 of 79	ENST00000357033.9	NP_003997.2	P11532

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9 link	c.2972A>G	p.Glu991Gly	missense_variant	Exon 23 of 79	1	NM_004006.3	ENSP00000354923.3		A0A075B6G3

Frequencies

GnomAD3 genomes

AF:

0.00000896

AC:

AN:

111644

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000550

AC:

AN:

181694

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000820

AC:

AN:

1097426

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362912

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26385

American (AMR)

AF:

0.00

AC:

AN:

35163

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19373

East Asian (EAS)

AF:

0.00

AC:

AN:

30169

South Asian (SAS)

AF:

0.00

AC:

AN:

54082

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40484

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4121

European-Non Finnish (NFE)

AF:

0.0000107

AC:

AN:

841600

Other (OTH)

AF:

0.00

AC:

AN:

46049

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000896

AC:

AN:

111644

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33818

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30796

American (AMR)

AF:

0.00

AC:

AN:

10386

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3557

South Asian (SAS)

AF:

0.00

AC:

AN:

2674

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6045

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53125

Other (OTH)

AF:

0.00

AC:

AN:

1491

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary dilated cardiomyopathy

Uncertain:1

Mar 11, 2015

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

DMD-related disorder

Uncertain:1

Nov 11, 2022

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The DMD c.2972A>G variant is predicted to result in the amino acid substitution p.Glu991Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/X-32486805-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Duchenne muscular dystrophy

Uncertain:1

Nov 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 991 of the DMD protein (p.Glu991Gly). This variant is present in population databases (rs747374618, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with DMD-related conditions. ClinVar contains an entry for this variant (Variation ID: 226048). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DMD protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

May 09, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.E991G variant (also known as c.2972A>G), located in coding exon 23 of the DMD gene, results from an A to G substitution at nucleotide position 2972. The glutamic acid at codon 991 is replaced by glycine, an amino acid with similar properties. Based on data from gnomAD, the G allele has an overall frequency of <0.01% (1/181694) total alleles studied, with 0 hemizygote(s) observed. The highest observed frequency was <0.01% (1/80685) of European (non- Finnish) alleles. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.30

.;T;.;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;.;D;D

M_CAP

Uncertain

0.25

MetaRNN

Uncertain

0.52

D;D;D;D

MetaSVM

Benign

-0.74

PhyloP100

7.1

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.1

.;D;.;D

REVEL

Benign

0.15

Sift

Uncertain

0.025

.;D;.;D

Sift4G

Uncertain

0.020

D;D;D;D

Polyphen

0.86

.;P;.;.

Vest4

0.59

MutPred

0.20

.;.;Gain of helix (P = 0.062);Gain of helix (P = 0.062);

MVP

0.56

MPC

0.017

ClinPred

0.75

GERP RS

5.1

gMVP

0.16

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over