rs140791274

Positions:

chrX-32287668-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP6BS2

The NM_004006.3(DMD):c.6151C>T(p.Arg2051Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000257 in 1,206,230 control chromosomes in the GnomAD database, including 1 homozygotes. There are 6 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2051Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000036 ( 1 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000025 ( 0 hom. 6 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 6.83

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 -4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.758

BP6

Variant X-32287668-G-A is Benign according to our data. Variant chrX-32287668-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 380270.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.

BS2

High Hemizygotes in GnomAdExome4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.6151C>T	p.Arg2051Trp	missense_variant	43/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.6151C>T	p.Arg2051Trp	missense_variant	43/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes

AF:

0.0000361

AC:

AN:

110798

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33038

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000969

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:

0.0000566

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000275

AC:

AN:

181816

Hom.:

AF XY:

0.0000300

AC XY:

AN XY:

66570

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1095432

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

360974

show subpopulations

Gnomad4 AFR exome

AF:

0.0000380

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000664

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000286

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000361

AC:

AN:

110798

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33038

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000969

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000566

Gnomad4 OTH

AF:

0.00

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2016	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. -

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

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jun 16, 2020

- -

Duchenne muscular dystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

.;T;.;.

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

D;.;D;D

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.76

D;D;D;D

MetaSVM

Benign

-0.74

MutationTaster

Benign

0.85

N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.2

.;N;.;N

REVEL

Benign

0.28

Sift

Benign

0.044

.;D;.;D

Sift4G

Uncertain

0.0060

D;D;D;D

Polyphen

0.99

.;D;.;.

Vest4

0.56

MVP

0.49

MPC

0.089

ClinPred

0.38

GERP RS

4.4

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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