rs148835707

Positions:

chrX-32468672-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_004006.3(DMD):c.2988A>G(p.Leu996Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000298 in 1,209,470 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 101 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 0.000063 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.00032 ( 0 hom. 100 hem. )

Consequence

DMD
NM_004006.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: -0.0920

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:

DMD (HGNC:):

DMD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant X-32468672-T-C is Benign according to our data. Variant chrX-32468672-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 285127.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}. Variant chrX-32468672-T-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.092 with no splicing effect.

BS2

High Hemizygotes in GnomAdExome4 at 100 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.2988A>G	p.Leu996Leu	synonymous_variant	23/79	ENST00000357033.9	NP_003997.2	P11532

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.2988A>G	p.Leu996Leu	synonymous_variant	23/79	1	NM_004006.3	ENSP00000354923.3		A0A075B6G3

Frequencies

GnomAD3 genomes

AF:

0.0000627

AC:

AN:

111657

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33827

show subpopulations

Gnomad AFR

AF:

0.0000325

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:

0.000113

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000604

AC:

AN:

182196

Hom.:

AF XY:

0.0000298

AC XY:

AN XY:

67148

show subpopulations

Gnomad AFR exome

AF:

0.000153

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:

0.000111

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000322

AC:

353

AN:

1097813

Hom.:

Cov.:

AF XY:

0.000275

AC XY:

100

AN XY:

363287

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.000412

Gnomad4 OTH exome

AF:

0.000130

GnomAD4 genome

AF:

0.0000627

AC:

AN:

111657

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33827

show subpopulations

Gnomad4 AFR

AF:

0.0000325

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:

0.000113

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000356

Hom.:

Bravo

AF:

0.000117

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 25, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 03, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 02, 2019	- -

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

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 17, 2017

- -

DMD-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 10, 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). -

Duchenne muscular dystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2020

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

5.4

DANN

Benign

0.77

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