rs1554108610

Positions:

• chr6-7582721-AAGTCCTG-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_004415.4(DSP):​c.5460_5466del​(p.Val1821SerfsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DSP NM_004415.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 18 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-7582721-AAGTCCTG-A is Pathogenic according to our data. Variant chr6-7582721-AAGTCCTG-A is described in ClinVar as [Pathogenic]. Clinvar id is 464965.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.5460_5466del	p.Val1821SerfsTer14	frameshift_variant	24/24	ENST00000379802.8	NP_004406.2
DSP	NM_001008844.3	c.3663_3669del	p.Val1222SerfsTer14	frameshift_variant	24/24		NP_001008844.1
DSP	NM_001319034.2	c.4131_4137del	p.Val1378SerfsTer14	frameshift_variant	24/24		NP_001305963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.5460_5466del	p.Val1821SerfsTer14	frameshift_variant	24/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.3663_3669del	p.Val1222SerfsTer14	frameshift_variant	24/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.4131_4137del	p.Val1378SerfsTer14	frameshift_variant	24/24			ENSP00000518230	A2

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 8 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 02, 2017

This sequence change deletes 7 nucleotides from exon 24 of the DSP mRNA (c.5460_5466delAGTCCTG), causing a frameshift at codon 1821. This creates a premature translational stop signal in the last exon of the DSP mRNA (p.Val1821Serfs*14). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1050 amino acids of the DSP protein. While this truncation has not been reported in the literature, a truncating variant located downstream in exon 24 has been reported to be deleterious (PMID: 11063735). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554108610; hg19: chr6-7582954;