rs1554107839

Positions:

• chr6-7577847-GAC-G

Variant summary

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

The NM_004415.4(DSP):​c.2947_2948del​(p.Thr983HisfsTer22) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.00

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-7577847-GAC-G is Pathogenic according to our data. Variant chr6-7577847-GAC-G is described in ClinVar as [Pathogenic]. Clinvar id is 464959.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.2947_2948del	p.Thr983HisfsTer22	frameshift_variant	21/24	ENST00000379802.8	NP_004406.2
DSP	NM_001008844.3	c.2947_2948del	p.Thr983HisfsTer22	frameshift_variant	21/24		NP_001008844.1
DSP	NM_001319034.2	c.2947_2948del	p.Thr983HisfsTer22	frameshift_variant	21/24		NP_001305963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.2947_2948del	p.Thr983HisfsTer22	frameshift_variant	21/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.2947_2948del	p.Thr983HisfsTer22	frameshift_variant	21/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.2947_2948del	p.Thr983HisfsTer22	frameshift_variant	21/24			ENSP00000518230	A2

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

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

Labcorp Genetics (formerly Invitae), Labcorp

Aug 27, 2021

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). This variant has not been reported in the literature in individuals with DSP-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Thr983Hisfs*22) in the DSP gene. It is expected to result in an absent or disrupted protein product. -

Arrhythmogenic right ventricular dysplasia 8 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 22, 2017

This sequence change deletes 2 nucleotides from exon 21 of the DSP mRNA (c.2947_2948delAC), causing a frameshift at codon 983. This creates a premature translational stop signal (p.Thr983Hisfs*22) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in DSP are known to be pathogenic (PMID: 16061754, 20716751, 24503780). 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)		0.010		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: rs1554107839; hg19: chr6-7578080;