chrX-33020189-C-G

Position:

chrX-33020189-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting

The ENST00000357033.9(DMD):c.43G>C(p.Asp15His) variant causes a missense change. The variant allele was found at a frequency of 0.0000111 in 1,172,799 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.0000066 ( 0 hom. 0 hem. )

Consequence

DMD
ENST00000357033.9 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.86

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 -1 ACMG points.

BS2

High Hemizygotes in GnomAd4 at 2 XL geneVariant has number of hemizygotes 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/exons	MANE	Protein	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.43G>C	p.Asp15His	missense_variant	2/79	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.43G>C	p.Asp15His	missense_variant	2/79	1	NM_004006.3	ENSP00000354923	P4

Frequencies

GnomAD3 genomes

AF:

0.0000536

AC:

AN:

111947

Hom.:

Cov.:

AF XY:

0.0000586

AC XY:

AN XY:

34155

show subpopulations

Gnomad AFR

AF:

0.000162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000953

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000615

AC:

AN:

162617

Hom.:

AF XY:

0.00

AC XY:

AN XY:

52013

show subpopulations

Gnomad AFR exome

AF:

0.0000856

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000660

AC:

AN:

1060852

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

332594

show subpopulations

Gnomad4 AFR exome

AF:

0.000234

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000224

GnomAD4 genome

AF:

0.0000536

AC:

AN:

111947

Hom.:

Cov.:

AF XY:

0.0000586

AC XY:

AN XY:

34155

show subpopulations

Gnomad4 AFR

AF:

0.000162

Gnomad4 AMR

AF:

0.0000953

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000529

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 12, 2015

The p.Asp15His variant in DMD has not been previously reported in individuals wi th cardiomyopathy and was absent from large population studies. Computational pr ediction tools and conservation analysis suggest that the variant may not impact the protein, though this information is not predictive enough to rule out patho genicity. In summary, the clinical significance of the p.Asp15His variant is unc ertain. -

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

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 21, 2020

- -

Duchenne muscular dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2023

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DMD protein function. ClinVar contains an entry for this variant (Variation ID: 228589). This variant has not been reported in the literature in individuals affected with DMD-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 15 of the DMD protein (p.Asp15His). -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2023

The p.D15H variant (also known as c.43G>C), located in coding exon 2 of the DMD gene, results from a G to C substitution at nucleotide position 43. The aspartic acid at codon 15 is replaced by histidine, an amino acid with similar properties. This variant has been detected in a cohort referred for dilated cardiomyopathy genetic testing (Mazzarotto F et al. Circulation. 2020 Feb;141(5):387-398). Based on data from gnomAD, the C allele has an overall frequency of 0.001084% (2/184470) total alleles studied, with 0 hemizygotes observed. The highest observed frequency was 0.01136% (2/17607) of African American alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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

Pathogenic

0.73

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.33

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

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

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

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.44

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

MetaSVM

Pathogenic

0.94

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.8

.;D;.;D;N;D;D

REVEL

Uncertain

0.58

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.0070

D;D;D;D;D;D;D

Polyphen

1.0, 0.87

.;D;.;.;.;.;P

Vest4

0.48

MutPred

0.33

.;.;Gain of MoRF binding (P = 0.0648);Gain of MoRF binding (P = 0.0648);Gain of MoRF binding (P = 0.0648);Gain of MoRF binding (P = 0.0648);.;

MVP

0.93

MPC

0.066

ClinPred

0.60

GERP RS

5.2

gMVP

0.44

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