rs200473206

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_004415.4(DSP):c.273+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000333 in 1,613,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00034 ( 0 hom. )

Consequence

DSP
NM_004415.4 splice_donor_5th_base, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:17B:1

Conservation

PhyloP100: 3.44

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 Uncertain_significance. Variant got 4 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
DSP	NM_004415.4 linkuse as main transcript	c.273+5G>A	splice_donor_5th_base_variant, intron_variant	ENST00000379802.8
DSP	NM_001008844.3 linkuse as main transcript	c.273+5G>A	splice_donor_5th_base_variant, intron_variant
DSP	NM_001319034.2 linkuse as main transcript	c.273+5G>A	splice_donor_5th_base_variant, intron_variant
DSP	NM_001406591.1 linkuse as main transcript	c.273+5G>A	splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.273+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_004415.4	P2	P15924-1

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000272

AC:

AN:

249858

Hom.:

AF XY:

0.000229

AC XY:

AN XY:

135146

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000656

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000522

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000337

AC:

493

AN:

1460816

Hom.:

Cov.:

AF XY:

0.000358

AC XY:

260

AN XY:

726700

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000377

Gnomad4 NFE exome

AF:

0.000417

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000289

AC:

AN:

152370

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000426

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000772

Hom.:

Bravo

AF:

0.000276

EpiCase

AF:

0.000545

EpiControl

AF:

0.000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:17Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 29, 2019	Variant classified as Uncertain Significance - Favor Benign. The c.273+5G>A variant in DSP has been reported in 1 individual with adolescent-onset VT, 1 individual with DCM, 1 individual with sinus bradycardia, 1 compound heterozygous individual with unspecified cardiomyopathy, and at least 3 individuals with ARVC (Basso 2006, Bauce 2011, Dal Ferra 2017, Mezzano 2016, Rigato 2013, te Rijdt 2017, LMM data). This variant has also been reported in ClinVar (Variation ID 163237) and has been identified in 68/125966 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200473206). This variant is located in the 5' splice region. Computational tools suggest a possible impact to splicing. However, analysis of RNA from patients carrying this variant did not identify aberrant transcripts (Basso 2006), which may indicate that splicing is not impacted. Alternatively, this may be the result of RNA degradation, which is a frequent consequence of abnormal splicing. In summary, the clinical significance of the c.273+5G>A variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 22, 2022	Variant summary: DSP c.273+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site and one predicts the variant weakens a 5' donor site. When mRNA transcripts from patient cells were examined, the variant did not appear to impact splicing, although very little protein was produced from the transcript even when cells were treated with NMD and protease inhibitors (Bliley_2021). The variant allele was found at a frequency of 0.00028 in 282064 control chromosomes (gnomAD, Basso_2006, Rigato_2013), predominantly at a frequency of 0.00052 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 21 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Cardiomyopathy (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.273+5G>A has been reported in the literature in individuals affected with Cardiomyopathy (e.g. Rigato_2013, van Lint_2019, Gigli_2019, Surmacz_2018, Marschall_2019, van Wijngaarden_2020, Bliley_2021). These data indicate that the variant may be associated with disease. Additional experiments using a 3D-engineeered heart tissue contractile shortening assay showed that the variant produced less than half of the DSP protein seen in controls and approximately half of the engineered heart tissues broke after removal from the culture wells. Those that could be assayed showed elevated diastolic stress and stretching of the engineered tissue (Bliley_2021). Seven ClinVar submitters have assessed the variant since 2014: all have classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This variant causes a G to A nucleotide substitution at the +5 position of intron 2 of the DSP gene. Computational splicing tools suggest that this variant may impact RNA splicing. An RNA study performed with cells from a carrier has not detected aberrant transcripts and showed only the wild-type transcript (PMID: 16774985; variant described as c.542+5G>A). This observation suggests that the variant does not impact splicing or may be the result of degradation of the aberrant transcripts. This variant has been reported in four individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 16774985, 21723241, Shestak et al. 2021, doi:10.15829/1560-4071-2021-4692) and in one individual afffected with dilated cardiomyopathy (PMID: 32826072). This variant has also been reported in compound heterozygous state with truncating variants in an individual affected with arrhythmogenic cardiomyopathy (PMID: 34290054) and in three unrelated individuals affected with Carvajal syndrome (OMIM 605676) (PMID: 34026522, Hoorntje et al. 2021, doi: 10.1101/2021.10.16.21264154). This variant occurs at an elevated frequency in the general population and has been identified in 79/281264 chromosomes (67/128380 non-Finnish European chromosomes) by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 16, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 18, 2023	This variant causes a G to A nucleotide substitution at the +5 position of intron 2 of the DSP gene. Computational splicing tools suggest that this variant may impact RNA splicing. An RNA study performed with cells from a carrier has not detected aberrant transcripts and showed only the wild-type transcript (PMID: 16774985; variant described as c.542+5G>A). This observation suggests that the variant does not impact splicing or may be the result of degradation of the aberrant transcripts. This variant has been reported in four individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 16774985, 21723241, Shestak et al. 2021, doi:10.15829/1560-4071-2021-4692) and in one individual afffected with dilated cardiomyopathy (PMID: 32826072). This variant has also been reported in compound heterozygous state with truncating variants in an individual affected with arrhythmogenic cardiomyopathy (PMID: 34290054) and in three unrelated individuals affected with Carvajal syndrome (OMIM 605676) (PMID: 34026522, Hoorntje et al. 2021, doi: 10.1101/2021.10.16.21264154). This variant occurs at an elevated frequency in the general population and has been identified in 79/281264 chromosomes (67/128380 non-Finnish European chromosomes) by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 04, 2022	The DSP c.273+5G>A variant (rs200473206), also known as c.542+5G>A, is reported in the literature in individuals affected with arrhythmogenic right ventricular cardiomyopathy and dilated cardiomyopathy (Basso 2006, Bauce 2011, Gigli 2019). This variant is reported in ClinVar (Variation ID: 163237), and is found in the non-Finnish European population with an allele frequency of 0.05% (67/128380 alleles) in the Genome Aggregation Database. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. However, given the lack of clinical and functional data, the significance of the c.273+5G>A variant is uncertain at this time. References: Basso et al. Ultrastructural evidence of intercalated disc remodelling in arrhythmogenic right ventricular cardiomyopathy: an electron microscopy investigation on endomyocardial biopsies. Eur Heart J. 2006; 27(15): 1847-1854. PMID: 16774985. Bauce et al. Clinical phenotype and diagnosis of arrhythmogenic right ventricular cardiomyopathy in pediatric patients carrying desmosomal gene mutations. Heart Rhythm. 2011; 8(11): 1686-1695. PMID: 21723241. Gigli M et al. Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy. J Am Coll Cardiol. 2019 Sep 17;74(11):1480-1490. PMID: 31514950731. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 2022	Identified independently and in conjunction with additional cardiogenetic variants in individuals referred for genetic testing at GeneDx, but segregation data are limited or absent at this time; Published cDNA analysis did not yield aberrant transcripts; the authors suggest this may be due to nonsense-mediated decay of the variant allele, although detection of only the wild-type allele would also occur if this variant did not affect splicing (Basso et al., 2006); In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Also known as c.542+5 G>A and IVS2+5 G>A; This variant is associated with the following publications: (PMID: 28759816, 30398466, 21723241, 26138720, 16774985, 24070718, 27097650, 28074886, 18382419, 28416588, 34426522, 30847666, 31514951, 31737537, 32277046, 31402444, 32372669) -

Arrhythmogenic right ventricular dysplasia 8

Uncertain:2

Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	May 04, 2023	The c.273+5G>A variant has previously been reported in multiple individuals with arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, and sinus bradycardia [PMID: 16774985, 21723241, 28416588, 27097650, 24070718, 28759816, 30847666, 31514951, 30398466,32277046, 34290054]. Multiple independent laboratories have deposited this variant as Variant of Uncertain Significance in the ClinVar database (Variation ID:163237). The c.273+5G>A variant is observed in 163 alleles (0.027% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2,TOPMed Freeze 8). The c.273+5G>A variant is located in the splice region after exon 2 of this 24-exon gene and is predicted to affect mRNA splicing (Splice AI =0.670 and TraP score = 0.902). The cDNA analysis of lymphocyte RNA from an individual carrying the c.273+5G>A revealed no aberrant transcripts suggesting a nonsense-mediated mRNA decay of the aberrant transcripts [PMID: 16774985]. In another study, the analysis did not reveal alternative mRNA splicing in hiPSC-derived cardiomyocytes from an individual carrying the c.273+5G>A and c.6687delA [PMID: 34290054]. Based on available evidence this c.273+5G>A variant identified in DSP is classified as a Variant of Uncertain Significance. -

Primary dilated cardiomyopathy;C0023976:Long QT syndrome

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Sep 29, 2014

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 28, 2022

This sequence change falls in intron 2 of the DSP gene. It does not directly change the encoded amino acid sequence of the DSP protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs200473206, gnomAD 0.05%). This variant has been observed in individual(s) with autosomal dominant arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy or sudden infant death syndrome, and/or autosomal recessive Carvajal syndrome (PMID: 16774985, 21723241, 28074886; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.542+5G>A. ClinVar contains an entry for this variant (Variation ID: 163237). Studies have shown that this variant alters DSP gene expression (PMID: 34290054). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). RNA analysis performed to evaluate the impact of this variant on mRNA splicing indicates it does not significantly alter splicing (PMID: 16774985, 34290054). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Arrhythmogenic right ventricular cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Aug 19, 2015

- -

Lethal acantholytic epidermolysis bullosa

Uncertain:1

Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Woolly hair-skin fragility syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Sep 29, 2014

- -

Woolly hair-skin fragility syndrome;C1843896:Arrhythmogenic right ventricular dysplasia 8;C1852127:Keratosis palmoplantaris striata 2;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C1864826:Lethal acantholytic epidermolysis bullosa;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 21, 2022

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

Cadd

Benign

Dann

Benign

0.94

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.22

Position offset: -5

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