rs141392048

Positions:

chrX-31204086-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PS1_ModerateBP4_StrongBP6_Very_StrongBS1BS2

The NM_004006.3(DMD):c.9682T>C(p.Phe3228Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000309 in 1,209,954 control chromosomes in the GnomAD database, including 1 homozygotes. There are 98 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., 46 hem., cov: 24)

Exomes 𝑓: 0.00017 ( 1 hom. 52 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 5.30

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 -18 ACMG points.

PS1

Transcript NM_004006.3 (DMD) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

BP4

Computational evidence support a benign effect (MetaRNN=0.011708409).

BP6

Variant X-31204086-A-G is Benign according to our data. Variant chrX-31204086-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 94856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-31204086-A-G is described in Lovd as [Likely_pathogenic]. Variant chrX-31204086-A-G is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00168 (188/111986) while in subpopulation AFR AF= 0.00565 (174/30800). AF 95% confidence interval is 0.00496. There are 0 homozygotes in gnomad4. There are 46 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 46 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.9682T>C	p.Phe3228Leu	missense_variant	67/79	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.9682T>C	p.Phe3228Leu	missense_variant	67/79	1	NM_004006.3	ENSP00000354923	P4

Frequencies

GnomAD3 genomes

AF:

0.00168

AC:

188

AN:

111934

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

34110

show subpopulations

Gnomad AFR

AF:

0.00566

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00132

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:

0.000563

AC:

103

AN:

183066

Hom.:

AF XY:

0.000385

AC XY:

AN XY:

67556

show subpopulations

Gnomad AFR exome

AF:

0.00623

Gnomad AMR exome

AF:

0.000620

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000527

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.000442

GnomAD4 exome

AF:

0.000169

AC:

186

AN:

1097968

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

AN XY:

363330

show subpopulations

Gnomad4 AFR exome

AF:

0.00515

Gnomad4 AMR exome

AF:

0.000653

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000356

Gnomad4 OTH exome

AF:

0.000499

GnomAD4 genome

AF:

0.00168

AC:

188

AN:

111986

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

AN XY:

34172

show subpopulations

Gnomad4 AFR

AF:

0.00565

Gnomad4 AMR

AF:

0.00132

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:

0.000158

Hom.:

Bravo

AF:

0.00212

ESP6500AA

AF:

0.00470

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000585

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2015	p.Phe3228Leu in exon 67 of DMD: This variant is not expected to have clinical si gnificance because it has been identified in 0.6% (49/8265) of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs141392048). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 02, 2014	- -

Duchenne muscular dystrophy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 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.

Mar 27, 2018

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Apr 17, 2019

- -

Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 02, 2021

- -

Primary dilated cardiomyopathy

Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

DMD-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 04, 2024

This variant is classified as 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

Sep 15, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

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

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

D;D;.;.;.;.;D;.;D;D;D;.;D;D;D

M_CAP

Benign

0.074

MetaRNN

Benign

0.012

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

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.95

N;N;.;N;N;N;.;N;.;N;N;N;N;N;N

REVEL

Benign

0.28

Sift

Benign

0.82

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

Sift4G

Benign

0.71

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

Polyphen

0.064, 0.99, 0.0010, 0.0040, 0.0

.;.;.;B;D;B;.;B;.;.;.;B;B;.;.

Vest4

0.35

MutPred

0.80

.;.;.;.;.;.;.;.;.;Gain of relative solvent accessibility (P = 0.1259);.;.;.;.;.;

MVP

0.90

MPC

0.019

ClinPred

0.039

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.58

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