rs41302885

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004415.4(DSP):c.6208G>A(p.Asp2070Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00425 in 1,614,150 control chromosomes in the GnomAD database, including 29 homozygotes. 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 0.0043 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 25 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:23

Conservation

PhyloP100: 8.15

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00889647).

BP6

Variant 6-7583470-G-A is Benign according to our data. Variant chr6-7583470-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44936.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=12, Benign=5}. Variant chr6-7583470-G-A is described in Lovd as [Benign]. Variant chr6-7583470-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00429 (654/152274) while in subpopulation AMR AF= 0.0133 (203/15306). AF 95% confidence interval is 0.0118. There are 4 homozygotes in gnomad4. There are 325 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4 link	c.6208G>A	p.Asp2070Asn	missense_variant	24/24	ENST00000379802.8	NP_004406.2	P15924-1B4DKX6
DSP	NM_001319034.2 link	c.4879G>A	p.Asp1627Asn	missense_variant	24/24		NP_001305963.1	P15924-3B4DKX6
DSP	NM_001008844.3 link	c.4411G>A	p.Asp1471Asn	missense_variant	24/24		NP_001008844.1	P15924-2B4DKX6Q4LE79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DSP	ENST00000379802.8 link	c.6208G>A	p.Asp2070Asn	missense_variant	24/24	1	NM_004415.4	ENSP00000369129.3	P15924-1
DSP	ENST00000418664.2 link	c.4411G>A	p.Asp1471Asn	missense_variant	24/24	1		ENSP00000396591.2	P15924-2
DSP	ENST00000710359.1 link	c.4879G>A	p.Asp1627Asn	missense_variant	24/24			ENSP00000518230.1

Frequencies

GnomAD3 genomes

AF:

0.00430

AC:

654

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000773

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0133

Gnomad ASJ

AF:

0.00807

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00500

Gnomad OTH

AF:

0.00575

GnomAD3 exomes

AF:

0.00410

AC:

1027

AN:

250724

Hom.:

AF XY:

0.00414

AC XY:

561

AN XY:

135608

show subpopulations

Gnomad AFR exome

AF:

0.000372

Gnomad AMR exome

AF:

0.00512

Gnomad ASJ exome

AF:

0.00804

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00101

Gnomad FIN exome

AF:

0.00213

Gnomad NFE exome

AF:

0.00581

Gnomad OTH exome

AF:

0.00458

GnomAD4 exome

AF:

0.00424

AC:

6201

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00432

AC XY:

3143

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.00447

Gnomad4 ASJ exome

AF:

0.00800

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00121

Gnomad4 FIN exome

AF:

0.00257

Gnomad4 NFE exome

AF:

0.00469

Gnomad4 OTH exome

AF:

0.00435

GnomAD4 genome

AF:

0.00429

AC:

654

AN:

152274

Hom.:

Cov.:

AF XY:

0.00436

AC XY:

325

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000770

Gnomad4 AMR

AF:

0.0133

Gnomad4 ASJ

AF:

0.00807

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.00501

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.00473

Hom.:

Bravo

AF:

0.00449

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00453

AC:

ExAC

AF:

0.00390

AC:

474

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00687

EpiControl

AF:

0.00616

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:23

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:8

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2019	This variant is associated with the following publications: (PMID: 25661095, 26073755, 26743238, 26498160, 24503780, 30972196, 31028937, 33232181) -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	DSP: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 29, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Uncertain:1Benign:6

Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Mar 26, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Given the information regarding prevalence in the control population, it is likely this variant is too common to contribute significantly to disease. There are no publications associating this variant with ARVC. The ARVC variant database lists this variant as ‘nonpathogenic’ (http://www.arvcdatabase.info). This is a semi conservative amino acid change with a negatively charged aspartic acid replaced with a neutral asparagine. Aspartic acid is semi conserved at residue 2070 in the DSP gene. In silico analysis (PolyPhen 2) predicts the amino acid change to be probably damaging to protein structure/function. There are no reported missense variants in nearby residues. In total the variant has been seen in 46 of 7,160 laboratory controls, published controls and individuals from publicly available population datasets. This variant is found in 39 of 4,280 (0.91%) European American individuals and 4 of 2,201 (0.81%) African American individuals listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 11/26/13). This variant is listed in dbSNP (rs41302885). Kapplinger et al (2011) did not observe the variant in 427 presumably healthy individuals that they studied. -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Mar 30, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 24, 2015	p.Asp2070Asn in exon 24 of DSP: This variant is not expected to have clinical si gnificance because it has been identified in 0.6% (393/65968) of European chromo somes, including 2 homozygotes, by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org; dbSNP rs41302885). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 01, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The heterozygous p.Asp2070Asn variant in DSP has been reported in 1 individual with arrhythmogenic cardiomyopathy (ACM), 2 with dilated cardiomyopathy (DCM), 1 with idiopathic ventricular fibrillation, and 1 suspected to have a genetic cardiovascular disease (PMID: 30820396, 25661095, 24503780, 26743238), and has been identified in 0.7910% (82/10366) of Ashkenazi Jewish chromosomes, 0.5636% (725/128630) of European (non-Finnish) chromosomes, and 0.5166% (183/35426) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs41302885). At least 3 affected individuals with this variant have an alternative molecular basis for DCM or ACM, suggesting that this variant may not be pathogenic (PMID: 24503780, 30820396; Variation ID: 45063). This variant has also been reported as benign, likely benign, and a VUS in ClinVar (Variation ID: 44936). The Aspartate (Asp) at position 2070 is highly conserved in mammals and evolutionary distant species, but one mammal (Wallaby) carries a Asparagine (Asn), supporting that this change at this position may be tolerated. Additional computational prediction tools do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP5 (Richards 2015). -

Arrhythmogenic right ventricular dysplasia 8

Uncertain:1Benign: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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jun 04, 2015	- -

Cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 29, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 08, 2018	- -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Genetics and Genomics Program, Sidra Medicine

- -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 23, 2024

- -

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

Feb 01, 2024

- -

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

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 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

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.16

T;.

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D

MetaRNN

Benign

0.0089

T;T

MetaSVM

Benign

-0.48

MutationAssessor

Benign

1.3

L;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.4

N;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.0040

D;T

Sift4G

Benign

0.21

T;T

Polyphen

1.0

D;.

Vest4

0.58

MVP

0.78

MPC

0.81

ClinPred

0.020

GERP RS

5.1

Varity_R

0.42

gMVP

0.65

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