rs727504443

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong

The NM_004415.4(DSP):c.939+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

DSP
NM_004415.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 9.86

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

arrhythmogenic right ventricular dysplasia 8
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
keratosis palmoplantaris striata 2
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Genomics England PanelApp
skin fragility-woolly hair-palmoplantar keratoderma syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Genomics England PanelApp, Ambry Genetics
arrhythmogenic cardiomyopathy with wooly hair and keratoderma
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen, Orphanet, Ambry Genetics
cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
lethal acantholytic epidermolysis bullosa
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
striate palmoplantar keratoderma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
severe dermatitis-multiple allergies-metabolic wasting syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

DSP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.01880223 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PP5

Variant 6-7565521-G-A is Pathogenic according to our data. Variant chr6-7565521-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 178282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4 link	c.939+1G>A	splice_donor_variant, intron_variant	Intron 7 of 23	ENST00000379802.8	NP_004406.2	P15924-1B4DKX6
DSP	NM_001319034.2 link	c.939+1G>A	splice_donor_variant, intron_variant	Intron 7 of 23		NP_001305963.1	P15924-3B4DKX6
DSP	NM_001008844.3 link	c.939+1G>A	splice_donor_variant, intron_variant	Intron 7 of 23		NP_001008844.1	P15924-2B4DKX6Q4LE79
DSP	NM_001406591.1 link	c.939+1G>A	splice_donor_variant, intron_variant	Intron 7 of 10		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8 link	c.939+1G>A		splice_donor_variant, intron_variant	Intron 7 of 23	1	NM_004415.4	ENSP00000369129.3		P15924-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461656

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111840

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41414

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00000505

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Jan 05, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Canonical splice site variant expected to result in aberrant splicing; Published functional studies demonstrate aberrant splicing leading to retention of the entire intron 7, which contains a premature termination codon within the N-terminal domain of the peptide (Whittock et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20738328, 25163546, 19095136, 24503780, 27532257, 10594734, 31317183, 32372669, 31402444, 31447099, 34352074, 30847666, 34135346, 20864495) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 02, 2016

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:provider interpretation

c.939+1G>A in DSP (NM_004415.2) Seen in a family with familial DCM. Testing done at Invitae. Given that this type of variation is typically pathogenic in this gene, the supporting experimental data, case data, and rarity, we consider this variant likely pathogenic and we feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Given that splice variants are known to be pathogenic in DSP and this specific variant has in vitro evidence for aberrant splicing, we did not do a thorough independent review of the data on the variant. Per the lab report, the variant "as been reported in the literature in patients with palmoplantar keratoderma, left dominant arrhythmogenic cardiomyopathy, arrhythmogenic right ventricular dysplasia, and dilated cardiomyopathy (PMID: 10594734, 19095136, 20864495, 24503780)." There is no variation at this nucleotide listed in the ExAC, which currently includes variant calls on >60,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in ExAC is >50x. -

Clinical Genetics, Academic Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiomyopathy

Pathogenic:2

Aug 02, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 22, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant causes a G to A nucleotide substitution at the +1 position of intron 7 of the DSP gene. A functional RNA study with a skin biopsy from a patient has shown that this variant causes the retention of intron 7, resulting in premature termination codon 25 amino acids downstream from the splice site. Only low levels of the mutant transcript were detected, indicating the variant leads to transcript degradation via nonsense-mediated mRNA decay (PMID: 10594734). This variant has been reported in an individual affected with striate palmoplantar keratoderma, and has been observed to segregate with disease in two relatives from the family (PMID: 10594734). This individual was later reported to be also affected with left-dominant arrhythmogenic cardiomyopathy (PMID: 19095136). Additionally, this variant has been identified in four other individuals with arrhythmogenic cardiomyopathy (PMIDs: 20864495, 36431211), at least three individuals with dilated cardiomyopathy (PMIDs: 24503780, 27532257; ClinVar SCV000924774.1, SCV000204706.4), an individual suspected of having hereditary cardiomyopathies (PMID: 35083019), an asymptomatic individual with a family history of arrhythmogenic cardiomyopathy (PMID: 36138163), and a healthy individual aged 70 years or older with no history of coronary heart disease (PMID: 34135346). This variant has been identified in 1/31370 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of DSP function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Arrhythmogenic right ventricular dysplasia 8

Pathogenic:2

Nov 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with arrhythmogenic right ventricular dysplasia 8 (MIM#607450) and other DSP-related cardiac disorders. (I) 0108 - This gene is associated with both recessive and dominant disease. Variants in this gene are usually inherited in a dominant manner, however rare reports of recessive inheritance have resulted in a more severe cardiac phenotype (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. In families with cardiomyopathies, reduced penetrance has been reported among family members aged 60-86 years (PMID: 36580316). (I) 0115 - Variants in this gene are known to have variable expressivity. Age-dependent penetrance and variable expressivity are well-described aspects of arrhythmogenic cardiomyopathy (PMID: 29062697). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Nested PCR of patient cDNA described the inclusion of intron 7 and a new stop codon twenty-five amino acids downstream. This new protein product would be predicted to undergo nonsense-mediated decay; however the relevant data was not shown by the authors and this information was interpreted with caution (PMID: 10594734). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (1 heterozygote, 0 homozygotes). (SP) 0703 - Other splice site variants comparable to the one identified in this case has moderate previous evidence for pathogenicity. Two variants (c.939+1G>T, c.939+2T>C) at this canonical splice site have been reported once each as pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported seven times as pathogenic and once as likely pathogenic (ClinVar). It has also been reported in an individual with arrhythmogenic right ventricular cardiomyopathy (PMID: 20864495), an individual with left-dominant arrhythmogenic cardiomyopathy (PMID: 19095136) and in a family with striate palmoplantar keratoderma with no mention of cardiac status (PMID: 10594734). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Cardiovascular phenotype

Pathogenic:2

Nov 15, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.939+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 7 of the DSP gene. This mutation was identified in a family with striate palmoplantar keratoderma; six individuals were heterozygous with 3 symptomatic. This mutation was identified in individuals with dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy; some individuals also had variants in other cardiac-related genes (Sen-Chowdhry S et al. J. Am. Coll. Cardiol., 2008 Dec;52:2175-87; Christensen AH et al. J. Med. Genet., 2010 Nov;47:736-44; Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Haas J et al. Eur. Heart J., 2015 May;36:1123-35a; Walsh R et al. Genet. Med., 2017 02;19:192-203). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. In addition, RNA studies have suggested that this variant results in aberrant splicing and nonsense-mediated decay (Whittock NV et al. J. Invest. Dermatol., 1999 Dec;113:940-6). Alterations in DSP that result in haploinsufficiency or protein truncation have been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM) (Fressart V et al. Europace.2010;12(6):861-8; Elliott P et al. Circ Cardiovasc Genet. 2010;3(4):314-22; Quarta G et al. Circulation. 2011;123(23):2701-9; Garcia-Pavia P et al. Heart. 2011;97(21):1744-52; Rasmussen TB et al. Clin Genet.2013;84(1):20-30; Pugh TJ et al.Genet Med.2014;16(8):601-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Feb 16, 2022

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma

Pathogenic:1

Jun 27, 2024

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Primary dilated cardiomyopathy;C0349788:Arrhythmogenic right ventricular cardiomyopathy

Pathogenic:1

Jan 05, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.939+1G>A variant in DSP has been reported in 2 individuals with ARVC, 1 wi th LDAC and 1 with palmoplantar hyperkeratosis (unknown cardiac status) (Whittoc k 1999, Sen Chowdry 2008, Christensen 2010, Asimaki 2009-refered to as 1218+1G>A ). This variant has been identified by our laboratory in 1 individual with DCM a nd segregated with disease in 1 affected relative. It was absent from large popu lation studies. This variant occurs in the invariant region (+/- 1,2) of the spl ice consensus sequence and studies have shown that it alters splicing, leading t o retention of intron 7 and a premature termination codon (Whittock 1999). Splic e site and other loss of function variants in DSP have been reported in patients with ARVC (http://arvcdatabase.info/). In summary, although additional studies are required to fully establish its clinical significance, the c.939+1G>A varian t is likely pathogenic. -

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

Pathogenic:1

Nov 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects a donor splice site in intron 7 of the DSP gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs727504443, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with arrhythmogenic right ventricular dysplasia, dilated cardiomyopathy, left dominant arrhythmogenic cardiomyopathy, and/or palmoplantar keratoderma (PMID: 10594734, 19095136, 20864495, 24503780). ClinVar contains an entry for this variant (Variation ID: 178282). Studies have shown that disruption of this splice site results in the retention of intron 7, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 10594734). For these reasons, this variant has been classified as Pathogenic. -

Keratosis palmoplantaris striata 2

Pathogenic:1

Nov 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

1.0

PhyloP100

9.9

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.99

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over