rs727504909
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4
The NM_004415.4(DSP):c.8576_8577del(p.Ser2859LeufsTer6) 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 Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
DSP
NM_004415.4 frameshift
NM_004415.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.40
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 2963 codons.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.8576_8577del | p.Ser2859LeufsTer6 | frameshift_variant | 24/24 | ENST00000379802.8 | NP_004406.2 | |
DSP | NM_001008844.3 | c.6779_6780del | p.Ser2260LeufsTer6 | frameshift_variant | 24/24 | NP_001008844.1 | ||
DSP | NM_001319034.2 | c.7247_7248del | p.Ser2416LeufsTer6 | frameshift_variant | 24/24 | NP_001305963.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.8576_8577del | p.Ser2859LeufsTer6 | frameshift_variant | 24/24 | 1 | NM_004415.4 | ENSP00000369129 | P2 | |
DSP | ENST00000418664.2 | c.6779_6780del | p.Ser2260LeufsTer6 | frameshift_variant | 24/24 | 1 | ENSP00000396591 | A2 | ||
DSP | ENST00000710359.1 | c.7247_7248del | p.Ser2416LeufsTer6 | frameshift_variant | 24/24 | ENSP00000518230 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 17, 2014 | Variant classified as Uncertain Significance - Favor Pathogenic. The Ser2859fs v ariant in DSP has not been reported in individuals with cardiomyopathy or in lar ge population studies. This frameshift variant is predicted to alter the protein ?s amino acid sequence beginning at position 2859 and leads to a premature termi nation codon 6 amino acids downstream, resulting in a loss of the last 6 amino a cids of the DSP protein and may not. It is unclear if this variant would undergo nonsense mediated decay and cause a loss of function variant. However, homozygo us variants that truncate the tail of the DSP protein have been reported in indi viduals with Carvajal syndrome and/or acantholytic epidermolysis bullosa (Cheong 2005, Jonkman 2005, Rasmussen 2013). Although this data supports that the Ser28 59fs variant may be pathogenic in homozygous configuration, additional studies a re needed to fully assess its clinical significance. - |
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 15, 2023 | - - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at