rs794728138
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PM4_Supporting
The NM_004415.4(DSP):c.935_937delTCT(p.Phe312del) variant causes a disruptive inframe deletion, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 31)
Consequence
DSP
NM_004415.4 disruptive_inframe_deletion, splice_region
NM_004415.4 disruptive_inframe_deletion, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.91
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 5 ACMG points.
PM1
In a repeat Spectrin 2 (size 103) in uniprot entity DESP_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_004415.4
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_004415.4. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| DSP | NM_004415.4 | c.935_937delTCT | p.Phe312del | disruptive_inframe_deletion, splice_region_variant | Exon 7 of 24 | ENST00000379802.8 | NP_004406.2 | |
| DSP | NM_001319034.2 | c.935_937delTCT | p.Phe312del | disruptive_inframe_deletion, splice_region_variant | Exon 7 of 24 | NP_001305963.1 | ||
| DSP | NM_001008844.3 | c.935_937delTCT | p.Phe312del | disruptive_inframe_deletion, splice_region_variant | Exon 7 of 24 | NP_001008844.1 | ||
| DSP | NM_001406591.1 | c.935_937delTCT | p.Phe312del | disruptive_inframe_deletion, splice_region_variant | Exon 7 of 11 | NP_001393520.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 27, 2013 | c.935_937delTCT: p.Phe312del (F312del) in exon 7 of the DSP gene (NM_004415.2). The normal sequence with the bases that are deleted in braces is: GCCT{TCT}CCgt.The c.935_937delTCT variant in the DSP gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The c.935_937delTCT variant results in an in-frame deletion of a Phenylalanine at codon 312 in the DSP gene. The c.935_937delTCT variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. One in-frame deletion has been reported in association with ARVC as well as a missense mutation in a neighboring codon (Ser299Arg). With the clinical and molecular information available at this time, we cannot definitively determine if c.935_937delTCT is a disease-causing mutation or a rare benign variant. The variant is found in ARVC panel(s). - |
| Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | - | - - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 07, 2019 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 199917). This variant is not present in population databases (ExAC no frequency). This variant, c.935_937delTCT, results in the deletion of 1 amino acid of the DSP protein (p.Phe312del), but otherwise preserves the integrity of the reading frame. - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 06, 2019 | The c.935_937delTCT variant (also known as p.F312del) is located in coding exon 7 of the DSP gene. This variant results from an in-frame TCT deletion at nucleotide positions 935 to 937. This results in the in-frame deletion of a phenylalanine residue at codon 312. This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
Name
Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at