rs142885240

Positions:

chr6-7581408-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The ENST00000379802.8(DSP):c.5218G>A(p.Glu1740Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,613,490 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00096 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 5 hom. )

Consequence

DSP
ENST00000379802.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:19

Conservation

PhyloP100: 3.21

Variant links:

Genes affected

DSP (HGNC:3052): (desmoplakin) This gene encodes a protein that anchors intermediate filaments to desmosomal plaques and forms an obligate component of functional desmosomes. Mutations in this gene are the cause of several cardiomyopathies and keratodermas, including skin fragility-woolly hair syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

DSP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08162171).

BP6

Variant 6-7581408-G-A is Benign according to our data. Variant chr6-7581408-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44926.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=11, Uncertain_significance=4}. Variant chr6-7581408-G-A is described in Lovd as [Benign]. Variant chr6-7581408-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00158 (2304/1461204) while in subpopulation MID AF= 0.0173 (100/5768). AF 95% confidence interval is 0.0146. There are 5 homozygotes in gnomad4_exome. There are 1151 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DSP	NM_004415.4 linkuse as main transcript	c.5218G>A	p.Glu1740Lys	missense_variant	23/24	ENST00000379802.8	NP_004406.2
DSP	NM_001008844.3 linkuse as main transcript	c.3583-1234G>A		intron_variant			NP_001008844.1
DSP	NM_001319034.2 linkuse as main transcript	c.4050+1168G>A		intron_variant			NP_001305963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.5218G>A	p.Glu1740Lys	missense_variant	23/24	1	NM_004415.4	ENSP00000369129	P2	P15924-1
DSP	ENST00000418664.2 linkuse as main transcript	c.3583-1234G>A		intron_variant		1		ENSP00000396591	A2	P15924-2
DSP	ENST00000710359.1 linkuse as main transcript	c.4050+1168G>A		intron_variant				ENSP00000518230	A2

Frequencies

GnomAD3 genomes

AF:

0.000959

AC:

146

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00134

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00142

AC:

356

AN:

251104

Hom.:

AF XY:

0.00156

AC XY:

212

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00212

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00105

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00187

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00158

AC:

2304

AN:

1461204

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

1151

AN XY:

726934

show subpopulations

Gnomad4 AFR exome

AF:

0.000360

Gnomad4 AMR exome

AF:

0.00263

Gnomad4 ASJ exome

AF:

0.00126

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000905

Gnomad4 FIN exome

AF:

0.000187

Gnomad4 NFE exome

AF:

0.00167

Gnomad4 OTH exome

AF:

0.00159

GnomAD4 genome

AF:

0.000959

AC:

146

AN:

152286

Hom.:

Cov.:

AF XY:

0.000913

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00229

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00134

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00166

Hom.:

Bravo

AF:

0.00125

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00123

AC:

150

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00234

EpiControl

AF:

0.00243

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:19

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:8

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2021	This variant is associated with the following publications: (PMID: 21606396, 31395126, 26230511, 23861362, 26656175, 27153395, 27435932, 24503780, 30821013) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	DSP: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 07, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 23, 2016	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not specified

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 20, 2020	The p.Glu1740Lys variant in DSP is classified as likely benign because it has been identified in 0.2% (73/35312) of Latino and 0.18% (229/129084) of European chromosomes, including 1 homozygous individual by gnomAD (http://gnomad.broadinstitute.org). It has also been reported in >10 individuals with a range of cardiomyopathy phenotypes (ARVC, DCM, HCM, RCM, Brugada syndrome, ventricular tachycardia), and it has segregated with Brugada syndrome in 1 affected relative from 1 family (Cox 2011, Allegue 2015, Bottillo 2016, LMM data). However, these diseases have different underlying molecular mechanisms, and furthermore, several of these probands were compound or double heterozygous with a presumed pathogenic variant. In summary, this variant is likely benign due to its elevated frequency in the general population, presence of phenotypes with different underlying molecular mechanisms in reported cases, as well as cases that had other more likely causative variants identified. ACMG/AMP Criteria applied: BS1, BP5, BP4. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jan 26, 2017	- -

Cardiomyopathy

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 14, 2021	- -

Primary dilated cardiomyopathy;C0018991:Hemiplegia;C0149931:Migraine

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 24, 2014

- -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Dept of Medical Biology, Uskudar University

Jan 08, 2024

Criteria: BS1 -

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Aug 01, 2016

Found in patient having exome sequencing for an unrelated indication. No known history of arrhythmogenic right ventricular dysplasia. -

Lethal acantholytic epidermolysis bullosa

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Woolly hair-skin fragility syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Arrhythmogenic right ventricular dysplasia 8

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2018

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. -

DSP-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2023

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Benign

-0.081

Eigen_PC

Benign

-0.072

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.85

M_CAP

Benign

0.033

MetaRNN

Benign

0.082

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

D;N

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.31

Sift

Uncertain

0.025

Sift4G

Benign

0.13

Polyphen

0.96

Vest4

0.71

MVP

0.77

MPC

0.34

ClinPred

0.034

GERP RS

5.1

Varity_R

0.14

gMVP

0.27

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