rs772574987
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_004415.4(DSP):c.7534G>T(p.Asp2512Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,614,128 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2512G) has been classified as Uncertain significance.
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.7534G>T | p.Asp2512Tyr | missense_variant | 24/24 | ENST00000379802.8 | |
DSP | NM_001319034.2 | c.6205G>T | p.Asp2069Tyr | missense_variant | 24/24 | ||
DSP | NM_001008844.3 | c.5737G>T | p.Asp1913Tyr | missense_variant | 24/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.7534G>T | p.Asp2512Tyr | missense_variant | 24/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.5737G>T | p.Asp1913Tyr | missense_variant | 24/24 | 1 | A2 | ||
DSP | ENST00000710359.1 | c.6205G>T | p.Asp2069Tyr | missense_variant | 24/24 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152246Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251488Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135918
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461882Hom.: 0 Cov.: 36 AF XY: 0.0000179 AC XY: 13AN XY: 727242
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152246Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74386
ClinVar
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 | This missense variant replaces aspartic acid with tyrosine at codon 2512 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). A functional study has shown that this variant does not affect the binding of DSP protein to intermediate filaments (PMID: 30354334). This variant has not been reported in individuals affected with cardiovascular disorders in the literature but has been observed in an healthy individual (PMID: 21636032). This variant has been identified in 2/251488 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. - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 28, 2022 | This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 2512 of the DSP protein (p.Asp2512Tyr). This variant is present in population databases (rs772574987, gnomAD 0.002%). This missense change has been observed in individual(s) with arrythmogenic right ventricular cardiomyopathy (PMID: 21636032). ClinVar contains an entry for this variant (Variation ID: 405229). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 25, 2023 | This missense variant replaces aspartic acid with tyrosine at codon 2512 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). A functional study has shown that this variant does not affect the binding of DSP protein to intermediate filaments (PMID: 30354334). This variant has not been reported in individuals affected with cardiovascular disorders in the literature but has been observed in an healthy individual (PMID: 21636032). This variant has been identified in 2/251488 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 11, 2023 | The p.D2512Y variant (also known as c.7534G>T), located in coding exon 24 of the DSP gene, results from a G to T substitution at nucleotide position 7534. The aspartic acid at codon 2512 is replaced by tyrosine, an amino acid with highly dissimilar properties. In a study of subjects with arrhythmogenic right ventricular dysplasia (ARVD), this alteration was identified in the healthy control cohort (Kapplinger JD et al. J. Am. Coll. Cardiol., 2011 Jun;57:2317-27). Additionally, in vitro analysis noted this alteration did not show significant effect on protein function (Favre B et al. Circ Genom Precis Med, 2018 Sep;11:e002241). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at