rs141805096
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_004415.4(DSP):c.4105G>A(p.Glu1369Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000707 in 1,613,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004415.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.4105G>A | p.Glu1369Lys | missense_variant | Exon 23 of 24 | ENST00000379802.8 | NP_004406.2 | |
DSP | NM_001319034.2 | c.4050+55G>A | intron_variant | Intron 23 of 23 | NP_001305963.1 | |||
DSP | NM_001008844.3 | c.3582+523G>A | intron_variant | Intron 23 of 23 | NP_001008844.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.4105G>A | p.Glu1369Lys | missense_variant | Exon 23 of 24 | 1 | NM_004415.4 | ENSP00000369129.3 | ||
DSP | ENST00000418664.2 | c.3582+523G>A | intron_variant | Intron 23 of 23 | 1 | ENSP00000396591.2 | ||||
DSP | ENST00000710359.1 | c.4050+55G>A | intron_variant | Intron 23 of 23 | ENSP00000518230.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152074Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250642Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135514
GnomAD4 exome AF: 0.0000753 AC: 110AN: 1461512Hom.: 0 Cov.: 32 AF XY: 0.0000619 AC XY: 45AN XY: 727014
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152074Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74278
ClinVar
Submissions by phenotype
not specified Uncertain:2
The Glu1369Lys variant in DSP has not been reported in individuals with cardiomy opathy, but has been identified in 1/8600 European American chromosomes by the N HLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs141805 096). Computational analyses (biochemical amino acid properties, conservation, A lignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an i mpact to the protein. At this time, additional information is needed to fully as sess the clinical significance of this variant. -
Variant summary: DSP c.4105G>A (p.Glu1369Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250642 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4105G>A has been reported in the literature in individuals affected with HCM, without strong evidence for causality (Lopes_2013). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014: four submitters classified the variant as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
This missense variant replaces glutamic acid with lysine at codon 1369 of the DSP protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant has been identified in 6/282028 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
p.Glu1369Lys (GAG>AAG): c.4105 G>A in exon 23 of the DSP gene (NM_004415.2). The E1369K variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The E1369K variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The E1369K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved within mammals. A missense mutation in a nearby residue (T1373A) has been reported in association with ARVC, supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The variant is found in CARDIOMYOPATHY panel(s). -
Cardiovascular phenotype Uncertain:1
The p.E1369K variant (also known as c.4105G>A), located in coding exon 23 of the DSP gene, results from a G to A substitution at nucleotide position 4105. The glutamic acid at codon 1369 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Woolly hair-skin fragility syndrome;C1843896:Arrhythmogenic right ventricular dysplasia 8;C1852127:Keratosis palmoplantaris striata 2;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C1864826:Lethal acantholytic epidermolysis bullosa;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Uncertain:1
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Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at