6-7581189-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004415.4(DSP):c.4999C>T(p.Gln1667Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
DSP
NM_004415.4 stop_gained
NM_004415.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 4.91
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 Pathogenic. Variant got 18 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 6-7581189-C-T is Pathogenic according to our data. Variant chr6-7581189-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 488983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.4999C>T | p.Gln1667Ter | stop_gained | 23/24 | ENST00000379802.8 | |
DSP | NM_001008844.3 | c.3582+1417C>T | intron_variant | ||||
DSP | NM_001319034.2 | c.4050+949C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.4999C>T | p.Gln1667Ter | stop_gained | 23/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.3582+1417C>T | intron_variant | 1 | A2 | ||||
DSP | ENST00000710359.1 | c.4050+949C>T | intron_variant | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 488983). This variant has not been reported in the literature in individuals affected with DSP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln1667*) in the DSP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). - |
Primary dilated cardiomyopathy;C0349788:Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 11, 2017 | The p.Gln1667X variant in DSP has not been previously reported in individuals wi th cardiomyopathy or in large population studies. This variant is located within exon 23 of DSP which undergoes alternative splicing resulting in two isoforms: one with a shorter and one with a longer form of this exon. This variant is only located in the coding region of the longer isoform. In that transcript, this no nsense variant leads to a premature termination codon at position 1667, which is predicted to lead to a truncated or absent protein. Loss-of-function variants i n the longer form of exon 23 have been observed in individuals with ARVC and/or DCM, suggesting that loss-of-function variants in this region are likely to be d isease causing (LMM data). In summary, although additional studies are required to fully establish its clinical significance, the p.Gln1667X variant is likely p athogenic. - |
Woolly hair-skin fragility syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 08, 2020 | This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 29, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33684294, 31638835, 31447099, Reza_2022_Cardiogenetics) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at