rs727504443

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePP3_StrongPP5_Very_Strong

The NM_004415.4(DSP):c.939+1G>A variant causes a splice donor 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

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 9.86

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 Pathogenic. Variant got 14 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.018686166 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PP3

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

PP5

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
DSP	NM_004415.4 linkuse as main transcript	c.939+1G>A	splice_donor_variant	ENST00000379802.8
DSP	NM_001008844.3 linkuse as main transcript	c.939+1G>A	splice_donor_variant
DSP	NM_001319034.2 linkuse as main transcript	c.939+1G>A	splice_donor_variant
DSP	NM_001406591.1 linkuse as main transcript	c.939+1G>A	splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.939+1G>A		splice_donor_variant		1	NM_004415.4	P2	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

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 02, 2016	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. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2023	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) -

Primary dilated cardiomyopathy;C0349788:Arrhythmogenic right ventricular cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 05, 2015

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

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 disrupted 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 introduces a premature termination codon (PMID: 10594734). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Arrhythmogenic right ventricular cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

- -

Cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 02, 2022

- -

Arrhythmogenic right ventricular dysplasia 8

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2010

- -

Keratosis palmoplantaris striata 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2010

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

1.0

MutationTaster

Benign

1.0

D;D

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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