rs41302885

chr6-7583470-G-Achr6-7583470-G-Cchr6-7583470-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2070H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (25 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:22
• Conservation: PhyloP100: 8.15

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]

ACMG classification

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: {Benign=6, Likely_benign=11, Uncertain_significance=1}. 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.6208G>A	p.Asp2070Asn	missense_variant	24/24	ENST00000379802.8
DSP	NM_001319034.2	c.4879G>A	p.Asp1627Asn	missense_variant	24/24
DSP	NM_001008844.3	c.4411G>A	p.Asp1471Asn	missense_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.6208G>A	p.Asp2070Asn	missense_variant	24/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.4411G>A	p.Asp1471Asn	missense_variant	24/24	1		A2
DSP	ENST00000710359.1	c.4879G>A	p.Asp1627Asn	missense_variant	24/24			A2

Frequencies

GnomAD3 genomes AF: 0.00430 AC: 654 AN: 152156 Hom.: 4 Cov.: 32

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.: 3 AF XY: 0.00414 AC XY: 561 AN XY: 135608

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.: 25 Cov.: 32 AF XY: 0.00432 AC XY: 3143 AN XY: 727236

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.: 4 Cov.: 32 AF XY: 0.00436 AC XY: 325 AN XY: 74464

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.: 1

Bravo AF: 0.00449

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00390 AC: 474

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00687

EpiControl AF: 0.00616

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:22

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:8

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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	- -
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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	DSP: BS2 -

not specified Uncertain:1 Benign: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. -
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	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). -
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	Mar 30, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 01, 2014	- -

Arrhythmogenic right ventricular dysplasia 8 Uncertain:1 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). 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

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

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Genetics and Genomics Program, Sidra Medicine

-

- -

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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

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. -

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 condition Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.16	T;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
MetaRNN	Benign	0.0089	T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
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	T
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

Other links and lift over

dbSNP: rs41302885; hg19: chr6-7583703; COSMIC: COSV105320934;