rs727505115

Variant names:

• chr6-7572069-G-A
• rs727505115
• NM_004415.4:c.2130+1G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-7572069-G-A
• chr6-7572069-G-C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004415.4(DSP):​c.2130+1G>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: DSP NM_004415.4 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 6.88
• Publications: 2 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.3, offset of 4, new splice context is: tagGTatct. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-7572069-G-A is Pathogenic according to our data. Variant chr6-7572069-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 179772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004415.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	NM_004415.4	MANE Select	c.2130+1G>A		splice_donor intron	N/A	NP_004406.2
	DSP	NM_001319034.2		c.2130+1G>A		splice_donor intron	N/A	NP_001305963.1
	DSP	NM_001008844.3		c.2130+1G>A		splice_donor intron	N/A	NP_001008844.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	ENST00000379802.8	TSL:1 MANE Select	c.2130+1G>A		splice_donor intron	N/A	ENSP00000369129.3
	DSP	ENST00000418664.3	TSL:1	c.2130+1G>A		splice_donor intron	N/A	ENSP00000396591.2
	DSP	ENST00000713911.1		n.*1610G>A		non_coding_transcript_exon	Exon 13 of 13	ENSP00000519210.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Apr 02, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Different pathogenic variant affecting the same nucleotide (2130+1 G>C) was reported in a patient with biventricular dilation and premature ventricular contractions; variant segregated with disease in 3 affected relatives (PMID: 20716751); Not observed at significant frequency in large population cohorts (gnomAD); Identified in a patient who underwent genetic testing for arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 30847666); This variant is associated with the following publications: (PMID: 20716751, 30847666)

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1

Jul 11, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2130+1G>A variant of the DSP gene is predicted to affect mRNA splicing and result in an absent or disrupted protein product. Loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). A similar variant (c.2130+1G>C) has been reported in 1 adult with biventricular dilation and PVCs and segregated with disease in 3 affected relatives (PMID: 20716751). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Therefore the c.2130+1G>A variant of the DSP gene is classified as likely pathogenic.

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

Mar 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 15 of the DSP gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with DSP-related conditions (PMID: 27532257, 30847666). ClinVar contains an entry for this variant (Variation ID: 179772). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Cardiomyopathy Pathogenic:1

Aug 21, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely 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 15 of the DSP gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 30847666). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Another variant at the same position, c.2130+1G>C (also known as IVS15+1G>C), has been observed in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257) and in another individual affected with idiopathic dilated cardiomyopathy (PMID: 20716751). Loss of DSP function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

Primary dilated cardiomyopathy Pathogenic:1

May 08, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 2130+1G>A variant in DSP has not been previously reported in individuals wit h cardiomyopathy or in large population studies. This variant occurs in the inv ariant region (+/- 1,2) of the splice consensus sequence and is predicted to cau se altered splicing leading to an abnormal or absent protein. A similar variant (2130+1G>C) has been reported in 1 adult with biventricular dilation and PVCs an d segregated with disease in 3 affected relatives (Elliott 2010). In summary, al though additional studies are required to fully establish its clinical significa nce, the 2130+1G>A variant is likely pathogenic.

DSP-related disorder Pathogenic:1

Mar 09, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DSP c.2130+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in an individual with arrhythmogenic right ventricular cardiomyopathy (supplementary file 2 - van Lint et al. 2019. PubMed ID: 30847666). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in DSP are expected to be pathogenic. This variant is interpreted as likely pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		6.9
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.95		Position offset: 3
DS_DL_spliceai		0.93		Position offset: -1

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

Other links and lift over

dbSNP: rs727505115; hg19: chr6-7572302; COSMIC: COSV65795037;