rs397516968
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM4BP6
The NM_004415.4(DSP):c.8481_8492del(p.Ser2843_Arg2846del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00000745 in 1,611,316 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 1 hom. )
Consequence
DSP
NM_004415.4 inframe_deletion
NM_004415.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.25
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 1 ACMG points.
PM4
?
Nonframeshift variant in NON repetitive region in NM_004415.4.
BP6
?
Variant 6-7585734-GTCCCGCTCCGGC-G is Benign according to our data. Variant chr6-7585734-GTCCCGCTCCGGC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44972.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.8481_8492del | p.Ser2843_Arg2846del | inframe_deletion | 24/24 | ENST00000379802.8 | |
DSP | NM_001008844.3 | c.6684_6695del | p.Ser2244_Arg2247del | inframe_deletion | 24/24 | ||
DSP | NM_001319034.2 | c.7152_7163del | p.Ser2400_Arg2403del | inframe_deletion | 24/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.8481_8492del | p.Ser2843_Arg2846del | inframe_deletion | 24/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.6684_6695del | p.Ser2244_Arg2247del | inframe_deletion | 24/24 | 1 | A2 | ||
DSP | ENST00000710359.1 | c.7152_7163del | p.Ser2400_Arg2403del | inframe_deletion | 24/24 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152002Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000201 AC: 5AN: 248526Hom.: 0 AF XY: 0.0000371 AC XY: 5AN XY: 134738
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GnomAD4 exome AF: 0.00000754 AC: 11AN: 1459314Hom.: 1 AF XY: 0.0000124 AC XY: 9AN XY: 725730
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152002Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74232
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
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 | Jan 11, 2024 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 11, 2013 | Ser2843_Arg2846del in exon 24 of DSP: This variant is not expected to have clini cal significance because it has been identified in 1.45% (62/4266) of African Am erican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). This in-frame deletion of four amino acids occurs within a section of repeating amino acids, which can result from several different DNA deletions, and is present in mammals (dolphin, opossum, and platy pus) and other evolutionarily distant species. - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | - - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 04, 2020 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 30, 2019 | This variant is associated with the following publications: (PMID: 27532257, 21636032) - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 30, 2020 | 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. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at