rs794728151
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM4PP3BP6_Very_StrongBS1
The NM_004415.4(DSP):c.8529_8540delTGGGTCCCGGAG(p.Ser2843_Arg2846del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000702 in 1,609,842 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000075 ( 0 hom. )
Consequence
DSP
NM_004415.4 disruptive_inframe_deletion
NM_004415.4 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.75
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 Benign. Variant got -9 ACMG points.
PM4
Nonframeshift variant in NON repetitive region in NM_004415.4.
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
BP6
Variant 6-7585788-CAGTGGGTCCCGG-C is Benign according to our data. Variant chr6-7585788-CAGTGGGTCCCGG-C is described in ClinVar as [Likely_benign]. Clinvar id is 199930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000748 (109/1457538) while in subpopulation AMR AF= 0.0025 (109/43668). AF 95% confidence interval is 0.00212. There are 0 homozygotes in gnomad4_exome. There are 44 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.8529_8540delTGGGTCCCGGAG | p.Ser2843_Arg2846del | disruptive_inframe_deletion | Exon 24 of 24 | ENST00000379802.8 | NP_004406.2 | |
DSP | NM_001319034.2 | c.7200_7211delTGGGTCCCGGAG | p.Ser2400_Arg2403del | disruptive_inframe_deletion | Exon 24 of 24 | NP_001305963.1 | ||
DSP | NM_001008844.3 | c.6732_6743delTGGGTCCCGGAG | p.Ser2244_Arg2247del | disruptive_inframe_deletion | Exon 24 of 24 | NP_001008844.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.8529_8540delTGGGTCCCGGAG | p.Ser2843_Arg2846del | disruptive_inframe_deletion | Exon 24 of 24 | 1 | NM_004415.4 | ENSP00000369129.3 | ||
DSP | ENST00000418664.2 | c.6732_6743delTGGGTCCCGGAG | p.Ser2244_Arg2247del | disruptive_inframe_deletion | Exon 24 of 24 | 1 | ENSP00000396591.2 | |||
DSP | ENST00000710359.1 | c.7200_7211delTGGGTCCCGGAG | p.Ser2400_Arg2403del | disruptive_inframe_deletion | Exon 24 of 24 | ENSP00000518230.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152184Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000396 AC: 97AN: 245192Hom.: 0 AF XY: 0.000249 AC XY: 33AN XY: 132794
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GnomAD4 exome AF: 0.0000748 AC: 109AN: 1457538Hom.: 0 AF XY: 0.0000607 AC XY: 44AN XY: 725024
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152304Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74478
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ClinVar
Significance: Likely benign
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Mar 27, 2014 | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Given that the variant is novel, and the type of variant we consider this variant a varian of uncertain significance. Variants in DSP have been associated with cardiomyopathy, primarily ARVC but also some cases of DCM (which may be left-sided ARVC). To our knowledge, the variant is novel. This is an in-frame deletion of four amino acids. Only one in-frame deletion has been reported before in associated with ARVC in HGMD. A neighboring in-frame deletion of the same size (p.Ser2843_Arg2846del) was observed in 1 of 427 "ostensibly healthy" controls studied by Kapplinger et al (2011) and a patient with DCM in the LMM cohort who also carried variants in MYH6, TTN, ABCC9, DSG2, and MYL3 (Pugh et al 2014). This variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 28th, 2014). However, this is not a reliable dataset for multi-nucleotide insertions or deletions. There variant is not listed in dbSNP (as of July 29th, 2014). - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2025 | - - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 29, 2018 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 26, 2020 | This variant is associated with the following publications: (PMID: 21636032, 27532257, 24503780) - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 24, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at