rs184154918

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004415.4(DSP):c.3923G>A(p.Arg1308Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000273 in 1,613,998 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1308W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 2 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 3.36

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070706904).

BP6

Variant 6-7580113-G-A is Benign according to our data. Variant chr6-7580113-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 178028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7580113-G-A is described in Lovd as [Likely_benign]. Variant chr6-7580113-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000506 (77/152230) while in subpopulation EAS AF= 0.0131 (68/5182). AF 95% confidence interval is 0.0106. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4 linkuse as main transcript	c.3923G>A	p.Arg1308Gln	missense_variant	23/24	ENST00000379802.8	NP_004406.2	P15924-1B4DKX6
DSP	NM_001319034.2 linkuse as main transcript	c.3923G>A	p.Arg1308Gln	missense_variant	23/24		NP_001305963.1	P15924-3B4DKX6
DSP	NM_001008844.3 linkuse as main transcript	c.3582+341G>A		intron_variant			NP_001008844.1	P15924-2B4DKX6Q4LE79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.3923G>A	p.Arg1308Gln	missense_variant	23/24	1	NM_004415.4	ENSP00000369129.3	P15924-1
DSP	ENST00000418664.2 linkuse as main transcript	c.3582+341G>A		intron_variant		1		ENSP00000396591.2	P15924-2
DSP	ENST00000710359.1 linkuse as main transcript	c.3923G>A	p.Arg1308Gln	missense_variant	23/24			ENSP00000518230.1

Frequencies

GnomAD3 genomes

AF:

0.000506

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0131

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00128

AC:

321

AN:

250626

Hom.:

AF XY:

0.00117

AC XY:

159

AN XY:

135600

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0170

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000249

AC:

364

AN:

1461768

Hom.:

Cov.:

AF XY:

0.000248

AC XY:

180

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00824

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000497

GnomAD4 genome

AF:

0.000506

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0131

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000428

Hom.:

Bravo

AF:

0.000604

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00121

AC:

147

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 06, 2014	p.Arg1308Gln in exon 23 of DSP: This variant is not expected to have clinical si gnificance because it has been identified in 1.5% (6/394) of Han Chinese chromos omes by the 1000 Genomes Project (dbSNP rs184154918) and in 1.7% (145/8730) of E ast Asian chromosomes by the Exome Aggregation Consortium (ExAC; http://exac.bro adinstitute.org). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	DSP: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 26585738) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 22, 2017	Variant summary: The c.3923G>A (p.Arg1308Gln) in the DSP gene is a missense change that involves the alteration of a non- conserved nucleotide and 5/5 in silico tools predict benign outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.001212 (146/ 120504 chrs tested), predominantly in individuals of East Asian descent (0.01648; 142/ 8618 chrs, including 1 homozygotes). The latter frequency exceeds the maximal expected allele frequency for a pathogenic variant in this gene (0.00001). Lastly, several reputable databases/diagnostic centers classified the variant of interest as Benign/Likely Benign. Taking together, the variant was classified as Benign. -

Cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 08, 2018	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Lethal acantholytic epidermolysis bullosa

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Woolly hair-skin fragility syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypertrophic cardiomyopathy;C0878544:Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jul 06, 2017

- -

Epidermolysis bullosa simplex due to plakophilin deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 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

0.088

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Benign

-0.0068

Eigen_PC

Benign

0.0071

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0071

MetaSVM

Benign

-0.34

MutationAssessor

Benign

1.1

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.61

REVEL

Benign

0.28

Sift

Benign

0.17

Sift4G

Benign

0.40

Polyphen

0.80

Vest4

0.59

MVP

0.72

MPC

0.44

ClinPred

0.027

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.065

gMVP

0.57

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