rs727502994

Positions:

• chr6-7581565-T-TAG

Variant summary

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

The NM_004415.4(DSP):​c.5378_5379dup​(p.Ala1794ArgfsTer25) variant causes a frameshift change involving the alteration of a non-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: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.22

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 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 109 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-7581565-T-TAG is Pathogenic according to our data. Variant chr6-7581565-T-TAG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 163231.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.5378_5379dup	p.Ala1794ArgfsTer25	frameshift_variant	23/24	ENST00000379802.8
DSP	NM_001008844.3	c.3583-1074_3583-1073dup		intron_variant
DSP	NM_001319034.2	c.4051-1074_4051-1073dup		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.5378_5379dup	p.Ala1794ArgfsTer25	frameshift_variant	23/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.3583-1074_3583-1073dup		intron_variant		1		A2
DSP	ENST00000710359.1	c.4051-1074_4051-1073dup		intron_variant				A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 15, 2013

The Ala1794fs variant in DSP has not been previously reported in individuals wit h cardiomyopathy and data from large population studies is insufficient to asses s its frequency. This frameshift variant is predicted to alter the protein?s ami no acid sequence beginning at position 1794 and lead to a premature termination codon 25 amino acids downstream. This alteration is then predicted to lead to a truncated protein. In summary, this variant is likely pathogenic, though additio nal studies are required to fully establish its clinical significance. -

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: rs727502994; hg19: chr6-7581798;