rs727502994

Positions:

• chr6-7581565-T-TAG

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_004415.4(DSP):​c.5378_5379dupAG variant causes a splice donor, intron 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 splice_donor, intron
• 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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.26624885 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.3, offset of 0 (no position change), new splice context is: gagGTattc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• 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	Protein	UniProt
DSP	NM_004415.4	c.5378_5379dupAG		splice_donor_variant, intron_variant		ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.4051-1074_4051-1073dupAG		intron_variant			NP_001305963.1
DSP	NM_001008844.3	c.3583-1074_3583-1073dupAG		intron_variant			NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.5378_5379dupAG		splice_donor_variant, intron_variant		1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.3583-1074_3583-1073dupAG		intron_variant		1		ENSP00000396591.2
DSP	ENST00000710359.1	c.4051-1074_4051-1073dupAG		intron_variant				ENSP00000518230.1

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;