X-32346053-C-G

Position:

chrX-32346053-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004006.3(DMD):c.5476G>C(p.Glu1826Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000173 in 1,207,945 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 62 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00075 ( 0 hom., 27 hem., cov: 23)

Exomes 𝑓: 0.00011 ( 0 hom. 35 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 5.18

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0076828003).

BP6

Variant X-32346053-C-G is Benign according to our data. Variant chrX-32346053-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228592.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=4, Uncertain_significance=1}. Variant chrX-32346053-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000754 (84/111379) while in subpopulation AFR AF= 0.00267 (82/30759). AF 95% confidence interval is 0.0022. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 27 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.5476G>C	p.Glu1826Gln	missense_variant	39/79	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.5476G>C	p.Glu1826Gln	missense_variant	39/79	1	NM_004006.3	ENSP00000354923	P4

Frequencies

GnomAD3 genomes

AF:

0.000728

AC:

AN:

111329

Hom.:

Cov.:

AF XY:

0.000745

AC XY:

AN XY:

33573

show subpopulations

Gnomad AFR

AF:

0.00257

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:

0.00

Gnomad OTH

AF:

0.00134

GnomAD3 exomes

AF:

0.000247

AC:

AN:

182511

Hom.:

AF XY:

0.000178

AC XY:

AN XY:

67301

show subpopulations

Gnomad AFR exome

AF:

0.00328

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000105

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000114

AC:

125

AN:

1096566

Hom.:

Cov.:

AF XY:

0.0000965

AC XY:

AN XY:

362584

show subpopulations

Gnomad4 AFR exome

AF:

0.00387

Gnomad4 AMR exome

AF:

0.0000285

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000739

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.000369

GnomAD4 genome

AF:

0.000754

AC:

AN:

111379

Hom.:

Cov.:

AF XY:

0.000803

AC XY:

AN XY:

33633

show subpopulations

Gnomad4 AFR

AF:

0.00267

Gnomad4 AMR

AF:

0.00

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:

0.00132

Alfa

AF:

0.000564

Hom.:

Bravo

AF:

0.000910

ESP6500AA

AF:

0.00209

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	DMD: BS1 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 25, 2017	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2015	Variant classified as Uncertain Significance - Favor Benign. The p.Glu1826Gln va riant in DMD has not been previously reported in individuals with cardiomyopathy or muscular dystrophy, but has been identified in 0.27% (23/8401) of African ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs140913030). Computational prediction tools and conservation analysi s do not provide strong support for or against an impact to the protein, althoug h 2 birds (scarlet macaw and rock pigeon) carry a glutamine (Gln) at this positi on, raising the possibility that this change may be tolerated. In summary, whil e the clinical significance of the p.Glu1826Gln variant is uncertain, its freque ncy and the presence of the variant amino acid in other species suggests that it is more likely to be benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 20, 2016	- -

DMD-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2019

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

.;T;.;.;T

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

D;.;D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.0077

T;T;T;T;T

MetaSVM

Benign

-0.58

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.3

.;N;.;N;D

REVEL

Benign

0.24

Sift

Uncertain

0.019

.;D;.;D;D

Sift4G

Uncertain

0.010

D;D;D;D;D

Polyphen

1.0

.;D;.;.;.

Vest4

0.21

MVP

0.78

MPC

0.055

ClinPred

0.091

GERP RS

5.8

gMVP

0.29

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