6-7584504-AT-A

Position:

• chr6-7584504-AT-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_004415.4(DSP):​c.7248delT​(p.Phe2416fs) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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 Pathogenic. Variant got 14 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 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-7584504-AT-A is Pathogenic according to our data. Variant chr6-7584504-AT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7584504-AT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.7248delT	p.Phe2416fs	frameshift_variant	24/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.5919delT	p.Phe1973fs	frameshift_variant	24/24		NP_001305963.1
DSP	NM_001008844.3	c.5451delT	p.Phe1817fs	frameshift_variant	24/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.7248delT	p.Phe2416fs	frameshift_variant	24/24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.5451delT	p.Phe1817fs	frameshift_variant	24/24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.5919delT	p.Phe1973fs	frameshift_variant	24/24			ENSP00000518230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Apr 10, 2024

This variant creates a premature termination codon in the last exon. The transcribed mRNA is predicted to escape nonsense-mediated decay and result in protein truncation. This variant was reported to be homozygous in one newborn with lethal acantholytic epidermolysis bullosa. It was heterozygous in the consanguineous parents, though no information was provided on their health (PMID: 20613772). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). -

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

Sep 21, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the DSP protein in which other variant(s) (p.Glu2728Glyfs*11) have been determined to be pathogenic (PMID: 21859740, 28527814; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 180181). This premature translational stop signal has been observed in individual(s) with autosomal recessive lethal acantholytic epidermolysis bullosa and/or clinical features of autosomal dominant arrhythmogenic cardiomyopathy (PMID: 20613772; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe2416Leufs*14) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 456 amino acid(s) of the DSP protein. -

Lethal acantholytic epidermolysis bullosa Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2010

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 27, 2017

The c.7248delT variant in the DSP gene has been reported previously in the homozygous state in an individual with acantholytic epidermolysis bullosa (Hobbs et al., 2010). The c.7248delT variant causes a frameshift starting with codon Phenylalanine 2416, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 14 of the new reading frame, denoted p.Phe2416LeufsX14. This variant is predicted to cause loss of normal protein function through protein truncation. The c.7248delT variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.7248delT as a pathogenic variant. -

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: rs730880024; hg19: chr6-7584737;