rs730880023

Positions:

• chr6-7577038-TTAAGG-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_004415.4(DSP):​c.2876_2877+3delAGGTA​(p.Lys959fs) variant causes a frameshift, splice donor, splice region, intron 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 (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DSP NM_004415.4 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.12

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 11 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 6-7577038-TTAAGG-T is Pathogenic according to our data. Variant chr6-7577038-TTAAGG-T is described in ClinVar as [Pathogenic]. Clinvar id is 180180.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.2876_2877+3delAGGTA	p.Lys959fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	20/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.2876_2877+3delAGGTA	p.Lys959fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	20/24		NP_001305963.1
DSP	NM_001008844.3	c.2876_2877+3delAGGTA	p.Lys959fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	20/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.2876_2877+3delAGGTA	p.Lys959fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	20/24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.2876_2877+3delAGGTA	p.Lys959fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	20/24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.2876_2877+3delAGGTA	p.Lys959fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	20/24			ENSP00000518230.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Lethal acantholytic epidermolysis bullosa Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2010

- -

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: rs730880023; hg19: chr6-7577271;