rs369017141

Positions:

chrX-32518040-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_004006.3(DMD):c.2260G>T(p.Gly754Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000256 in 1,208,698 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 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 0.00013 ( 0 hom., 5 hem., cov: 23)

Exomes 𝑓: 0.000015 ( 0 hom. 4 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.07

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.40866858).

BP6

Variant X-32518040-C-A is Benign according to our data. Variant chrX-32518040-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 519101.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.2260G>T	p.Gly754Cys	missense_variant	18/79	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.2260G>T	p.Gly754Cys	missense_variant	18/79	1	NM_004006.3	ENSP00000354923	P4

Frequencies

GnomAD3 genomes

AF:

0.000134

AC:

AN:

111557

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

33759

show subpopulations

Gnomad AFR

AF:

0.000456

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:

0.000664

GnomAD3 exomes

AF:

0.0000327

AC:

AN:

183225

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

67729

show subpopulations

Gnomad AFR exome

AF:

0.000380

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

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:

0.0000146

AC:

AN:

1097141

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

362559

show subpopulations

Gnomad4 AFR exome

AF:

0.000455

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.000134

AC:

AN:

111557

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

33759

show subpopulations

Gnomad4 AFR

AF:

0.000456

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:

0.000664

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000147

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 2023

The p.G754C variant (also known as c.2260G>T), located in coding exon 18 of the DMD gene, results from a G to T substitution at nucleotide position 2260. The glycine at codon 754 is replaced by cysteine, an amino acid with highly dissimilar properties. Based on data from gnomAD, the T allele has an overall frequency of 0.005% (10/205082) total alleles studied, with 4 hemizygotes observed. The highest observed frequency was 0.047% (9/19042) of African/ African American alleles. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Duchenne muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

.;T;.;.;T

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

D;.;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.41

T;T;T;T;T

MetaSVM

Uncertain

0.18

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.56

.;N;.;N;D

REVEL

Benign

0.20

Sift

Benign

0.095

.;T;.;T;D

Sift4G

Uncertain

0.033

D;D;D;D;D

Polyphen

1.0, 0.98

.;D;.;.;D

Vest4

0.81

MVP

0.84

MPC

0.12

ClinPred

0.22

GERP RS

5.1

gMVP

0.37

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