6-7582926-TGAGA-TGA

Position:

• chr6-7582926-TGAGA-TGA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004415.4(DSP):​c.5673_5674del​(p.Lys1892GlufsTer4) 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: 8.19

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 Pathogenic. Variant got 12 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 96 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-7582926-TGA-T is Pathogenic according to our data. Variant chr6-7582926-TGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 464968.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.5673_5674del	p.Lys1892GlufsTer4	frameshift_variant	24/24	ENST00000379802.8
DSP	NM_001008844.3	c.3876_3877del	p.Lys1293GlufsTer4	frameshift_variant	24/24
DSP	NM_001319034.2	c.4344_4345del	p.Lys1449GlufsTer4	frameshift_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.5673_5674del	p.Lys1892GlufsTer4	frameshift_variant	24/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.3876_3877del	p.Lys1293GlufsTer4	frameshift_variant	24/24	1		A2
DSP	ENST00000710359.1	c.4344_4345del	p.Lys1449GlufsTer4	frameshift_variant	24/24			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;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 24, 2018

This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the DSP gene (p.Lys1892Glufs*4). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 978 amino acids of the DSP protein. This variant has not been reported in the literature in individuals with a DSP-related disease. A different truncation downstream of this variant (c.7901delG) has been determined to be pathogenic (PMID: 11063735). This suggests that deletion of this region of the DSP protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1487814687; hg19: chr6-7583159;