rs121912998

Positions:

• chr6-7542003-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_004415.4(DSP):​c.88G>A​(p.Val30Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,595,514 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V30V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:5 B:22
• Conservation: PhyloP100: -0.807

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-AS1 (HGNC:56039): (DSP antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03806615).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00136 (1956/1443186) while in subpopulation MID AF= 0.00835 (48/5746). AF 95% confidence interval is 0.00647. There are 4 homozygotes in gnomad4_exome. There are 1110 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.88G>A	p.Val30Met	missense_variant	1/24	ENST00000379802.8	NP_004406.2
DSP-AS1	NR_183331.1	n.39-950C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.88G>A	p.Val30Met	missense_variant	1/24	1	NM_004415.4	ENSP00000369129	P2
DSP-AS1	ENST00000690863.2	n.344+768C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 152210 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00159 AC: 331 AN: 208172 Hom.: 3 AF XY: 0.00190 AC XY: 216 AN XY: 113510

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000990

Gnomad ASJ exome AF: 0.000550

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00433

Gnomad FIN exome AF: 0.000164

Gnomad NFE exome AF: 0.00185

Gnomad OTH exome AF: 0.00154

GnomAD4 exome AF: 0.00136 AC: 1956 AN: 1443186 Hom.: 4 Cov.: 32 AF XY: 0.00155 AC XY: 1110 AN XY: 716308

Gnomad4 AFR exome AF: 0.000182

Gnomad4 AMR exome AF: 0.000945

Gnomad4 ASJ exome AF: 0.000350

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00416

Gnomad4 FIN exome AF: 0.000178

Gnomad4 NFE exome AF: 0.00128

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152328 Hom.: 1 Cov.: 33 AF XY: 0.00138 AC XY: 103 AN XY: 74494

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00154

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00192 Hom.: 2

Bravo AF: 0.00123

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00187 AC: 16

ExAC AF: 0.00161 AC: 193

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:5 Benign:22

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 11, 2021	Variant summary: DSP c.88G>A (p.Val30Met) results in a 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 0.0016 in 212604 control chromosomes, predominantly at a frequency of 0.0043 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 22 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.0002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.88G>A has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (e.g. Yang_2006, Bauce_2010, Xu_2010, Rasmussen_2013, Rasmussen_2013, Bhonsale_2013, Rigato_2013). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Rasmussen_2012). Fourteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign/likely benign n=9, VUS n=3). Based on the evidence outlined above, the variant was classified as benign. -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 03, 2015	p.Val30Met in exon 1 of DSP: This variant is not expected to have clinical signi ficance due to a lack of conservation across species, including mammals. Of note , multiple mammals, including several primates, have a methionine (Met) at this position. This strongly argues against a disease causing role, though a modifyin g effect cannot be excluded. In addition, it has been identified in 0.6% (57/99 98) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs12192998). Of note, this variant has been publ ished by several studies (http://arvcdatabase.info/), though the data provided b y these studies is uninformative. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Feb 06, 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. Based on the data reviewed below, we consider this a variant of uncertain significance. This variant has been identified in multiple probands with ARVC and in one SCICD center patient with conduction system disease, biventricular dysfunction and a history of SCD. Yang et al (2006) first reported the variant in an individual with ARVC in a publication that only reports on DSP variants. In all other published cases this variant occurs with additional variants. Bauce et al (2010) identified an individual with ARVC and two DSP variants, p.Val30Met and p.Arg2541Lys. Each variant was detected in isolation in separate affected family members. Xu et al (2010) report a proband with the p.Val30Met variant as well as a nonsense and a missense variant in the PKP2 gene. This is a conservative amino acid change with the replacement on a nonpolar Valine with a nonpolar Methionine. Valine is not conserved across species and several species harbor a Methionine at this codon. In vitro studies reported by Yang et al (2006) showed that when this variant is present desmoplakin is trapped in the cytoplasm and fails to localize to the cell membrane. In total the variant has been seen in 21 of 9109 published controls and publicly available general population samples (as of 12/6/14). Across available publications the variant is absent in 1150 presumably healthy control individuals. However, more recently Kapplinger et al (2011) reported the variant in 1 of 427 presumably healthy individuals and the variant is reported in 16 of 4,269 European individuals in the NHLBI Exome Sequencing Project dataset and 0 of 2169 African American individuals (as of 2/6/14). It is also reported in dbSNP (rs 121912998), though this seems to point to the NHLBI data. It was also seen in 4 of 1094 individuals in the 1000 genomes low coverage data. -

not provided Uncertain:1 Benign:5

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 24, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	DSP: BS2 -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2020	This variant is associated with the following publications: (PMID: 32268277, 31028938, 25637381, 16917092, 20152563, 21636032, 23137101, 23671136, 24070718, 20129281, 23861362, 26656175, 27153395, 26332594, 26569459, 23299917, 28473349, 25985138, 27435932, 28798025, 31019283, 31402444, 33232181) -

Arrhythmogenic right ventricular dysplasia 8 Uncertain:2 Benign:2

Uncertain significance, no assertion criteria provided	literature only	OMIM	Sep 15, 2006	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 21, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

Cardiomyopathy Pathogenic:1 Benign:2

Pathogenic, no assertion criteria provided	clinical testing	Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences	Mar 27, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 14, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 27, 2018	- -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1 Benign:2

Likely benign, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 25, 2015	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Right ventricular cardiomyopathy Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Dec 13, 2013

- -

Keratosis palmoplantaris striata 2 Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Likely pathogenic. -

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

Feb 05, 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

Jan 31, 2024

- -

Lethal acantholytic epidermolysis bullosa Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Woolly hair-skin fragility syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2018

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. -

DSP-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 12, 2022

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	0.066
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	0.014
DANN	Benign	0.93
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0053	N
LIST_S2	Benign	0.59	T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.038	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.69	N;N
MutationTaster	Benign	2.5e-7	A;A
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.40	N;N
REVEL	Uncertain	0.39
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.13
MVP		0.99
MPC		0.22
ClinPred		0.0093	T
GERP RS		-7.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.034
gMVP		0.20

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: rs121912998; hg19: chr6-7542236;