rs17133512
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BA1
The NM_004415.4(DSP):c.1dup(p.Met1AsnfsTer?) variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,609,250 control chromosomes in the GnomAD database, including 19,165 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.17 ( 2453 hom., cov: 30)
Exomes 𝑓: 0.15 ( 16712 hom. )
Consequence
DSP
NM_004415.4 5_prime_UTR
NM_004415.4 5_prime_UTR
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.29
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.
BP6
?
Variant 6-7541915-C-CA is Benign according to our data. Variant chr6-7541915-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36015.We mark this variant Likely_benign, oryginal submissions are: {Benign=12, Uncertain_significance=1}.
BA1
?
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.1dup | p.Met1AsnfsTer? | 5_prime_UTR_variant | 1/24 | ENST00000379802.8 | |
DSP-AS1 | NR_183331.1 | n.39-863_39-862insT | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.1dup | p.Met1AsnfsTer? | 5_prime_UTR_variant | 1/24 | 1 | NM_004415.4 | P2 | |
DSP-AS1 | ENST00000690863.2 | n.344+855_344+856insT | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.173 AC: 26256AN: 152080Hom.: 2450 Cov.: 30
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GnomAD3 exomes AF: 0.167 AC: 38677AN: 231420Hom.: 3569 AF XY: 0.161 AC XY: 20455AN XY: 127368
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GnomAD4 exome AF: 0.146 AC: 212018AN: 1457052Hom.: 16712 Cov.: 32 AF XY: 0.144 AC XY: 104253AN XY: 724520
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GnomAD4 genome ? AF: 0.173 AC: 26267AN: 152198Hom.: 2453 Cov.: 30 AF XY: 0.175 AC XY: 13040AN XY: 74410
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:15
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:8
Benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 20, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 24, 2019 | Variant summary: DSP c.1dupA is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.17 in 231420 control chromosomes in the gnomAD database, including 3569 homozygotes. The observed variant frequency is approximately 6685.078 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.1dupA has been reported in the literature in individuals affected with Cardiomyopathy. These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 03, 2010 | The variant has been reported in dbSNP without frequency information (rs17133512 ). Classified as benign based on high allele frequency (0.162, n=290 chromosomes ) in ARVC probands tested at the LMM. In addition, the fraction of probands carr ying the -1_1insA variant matches the expected detection rate for ARVC (~50%), f urther supporting a benign role. - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Cardiomyopathy Benign:2
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 09, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Cohesion Phenomics | Sep 23, 2022 | - - |
Arrhythmogenic right ventricular dysplasia 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Sep 26, 2016 | - - |
Arrhythmogenic right ventricular cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Lethal acantholytic epidermolysis bullosa Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Woolly hair-skin fragility syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 22, 2015 | Internal frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance - |
Computational scores
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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