rs375919492
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_004415.4(DSP):c.4514C>T(p.Ala1505Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,613,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1505T) has been classified as Uncertain significance.
Frequency
Consequence
NM_004415.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.4514C>T | p.Ala1505Val | missense_variant | 23/24 | ENST00000379802.8 | |
DSP | NM_001008844.3 | c.3582+932C>T | intron_variant | ||||
DSP | NM_001319034.2 | c.4050+464C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.4514C>T | p.Ala1505Val | missense_variant | 23/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.3582+932C>T | intron_variant | 1 | A2 | ||||
DSP | ENST00000710359.1 | c.4050+464C>T | intron_variant | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152116Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000641 AC: 16AN: 249492Hom.: 0 AF XY: 0.0000666 AC XY: 9AN XY: 135096
GnomAD4 exome AF: 0.0000431 AC: 63AN: 1461710Hom.: 0 Cov.: 32 AF XY: 0.0000481 AC XY: 35AN XY: 727142
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74410
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 12, 2015 | Variant classified as Uncertain Significance - Favor Benign. The p.Ala1505Val va riant in DSP has not been previously reported in individuals with cardiomyopathy , but has been identified in 6/65984 European chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs375919492). Alanine (Ala) at position 1505 is not conserved in evolution and 2 mammals and 1 amphib ian (squirrel, Wedell seal, and X. tropicalis) carry a valine (Val), raising the possibility that this change may be tolerated. Although this suggests that the variant may not impact the protein, this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Al a1505Val variant is uncertain, these data suggest that it is more likely to be b enign. - |
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 | Dec 18, 2023 | This missense variant replaces alanine with valine at codon 1505 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20857253). This variant has been identified in 19/280894 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. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 06, 2023 | This missense variant replaces alanine with valine at codon 1505 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20857253). This variant has been identified in 19/280894 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 | Feb 04, 2022 | The p.A1505V variant (also known as c.4514C>T), located in coding exon 23 of the DSP gene, results from a C to T substitution at nucleotide position 4514. The alanine at codon 1505 is replaced by valine, an amino acid with similar properties. This variant has been detected in a cohort of cases with confirmed or suspected arrhythmogenic right ventricular cardiomyopathy; however, details were limited (Tan BY et al. J Cardiovasc Transl Res, 2010 Dec;3:663-73). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
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 01, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at