rs28715870

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004006.3(DMD):c.4162T>G(p.Phe1388Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00498 in 1,208,952 control chromosomes in the GnomAD database, including 158 homozygotes. There are 1,659 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.026 ( 89 hom., 777 hem., cov: 22)

Exomes 𝑓: 0.0029 ( 69 hom. 882 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 1.47

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022250712).

BP6

Variant X-32411823-A-C is Benign according to our data. Variant chrX-32411823-A-C is described in ClinVar as [Benign]. Clinvar id is 94615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32411823-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0837 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.4162T>G	p.Phe1388Val	missense_variant	30/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.4162T>G	p.Phe1388Val	missense_variant	30/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes

AF:

0.0256

AC:

2846

AN:

111321

Hom.:

Cov.:

AF XY:

0.0227

AC XY:

762

AN XY:

33519

show subpopulations

Gnomad AFR

AF:

0.0860

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0142

Gnomad ASJ

AF:

0.00189

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00339

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00418

Gnomad NFE

AF:

0.000452

Gnomad OTH

AF:

0.0200

GnomAD3 exomes

AF:

0.00767

AC:

1403

AN:

182914

Hom.:

AF XY:

0.00539

AC XY:

364

AN XY:

67584

show subpopulations

Gnomad AFR exome

AF:

0.0892

Gnomad AMR exome

AF:

0.00577

Gnomad ASJ exome

AF:

0.00120

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00105

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000319

Gnomad OTH exome

AF:

0.00376

GnomAD4 exome

AF:

0.00287

AC:

3153

AN:

1097580

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

882

AN XY:

363016

show subpopulations

Gnomad4 AFR exome

AF:

0.0855

Gnomad4 AMR exome

AF:

0.00662

Gnomad4 ASJ exome

AF:

0.00150

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00122

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000270

Gnomad4 OTH exome

AF:

0.00697

GnomAD4 genome

AF:

0.0257

AC:

2864

AN:

111372

Hom.:

Cov.:

AF XY:

0.0231

AC XY:

777

AN XY:

33580

show subpopulations

Gnomad4 AFR

AF:

0.0865

Gnomad4 AMR

AF:

0.0142

Gnomad4 ASJ

AF:

0.00189

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00302

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000452

Gnomad4 OTH

AF:

0.0198

Alfa

AF:

0.00447

Hom.:

190

Bravo

AF:

0.0292

ESP6500AA

AF:

0.0900

AC:

345

ESP6500EA

AF:

0.000595

AC:

ExAC

AF:

0.00872

AC:

1059

EpiCase

AF:

0.000327

EpiControl

AF:

0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Phe1388Val in exon 30 of DMD: This variant is not expected to have clinical si gnificance because it has been identified in 9% (345/3833) of African American c hromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/E VS/; dbSNP rs28715870). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 30, 2020	Variant summary: DMD c.4162T>G (p.Phe1388Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0077 in 182914 control chromosomes in the gnomAD database, including 33 homozygotes and 364 hemizygotes. The observed variant frequency is approximately 695 fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophinopathies phenotype (1.1e-05), strongly suggesting that the variant is benign. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 12, 2021	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 04, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 24, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 21, 2017

- -

Dilated cardiomyopathy 3B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Duchenne muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2016

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

Benign

0.048

BayesDel_addAF

Benign

-0.92

BayesDel_noAF

Benign

-1.0

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.22

.;T;.;.

FATHMM_MKL

Benign

0.087

LIST_S2

Benign

0.61

T;.;T;T

MetaRNN

Benign

0.0022

T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.32

PROVEAN

Benign

0.020

.;N;.;N

REVEL

Benign

0.024

Sift

Benign

0.26

.;T;.;T

Sift4G

Benign

0.28

T;T;T;T

Polyphen

0.0

.;B;.;.

Vest4

0.055

MVP

0.15

MPC

0.016

ClinPred

0.0017

GERP RS

3.1

gMVP

0.081

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