rs727504518
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_004415.4(DSP):āc.1484T>Cā(p.Val495Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V495M) has been classified as Likely benign.
Frequency
Consequence
NM_004415.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.1484T>C | p.Val495Ala | missense_variant | 12/24 | ENST00000379802.8 | |
DSP | NM_001319034.2 | c.1484T>C | p.Val495Ala | missense_variant | 12/24 | ||
DSP | NM_001008844.3 | c.1484T>C | p.Val495Ala | missense_variant | 12/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.1484T>C | p.Val495Ala | missense_variant | 12/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.1484T>C | p.Val495Ala | missense_variant | 12/24 | 1 | A2 | ||
DSP | ENST00000710359.1 | c.1484T>C | p.Val495Ala | missense_variant | 12/24 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461894Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727248
GnomAD4 genome ? Cov.: 32
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 | Nov 05, 2013 | The Val495Ala variant in DSP has not been previously reported in any other famil ies with HCM or in large population studies. Computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide strong su pport for or against an impact to the protein. Additional information is needed to fully assess the clinical significance of the Val495Ala variant. - |
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 | Feb 05, 2024 | This missense variant replaces valine with alanine at codon 495 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 who also carried a pathogenic variant in the MYBPC3 gene that could explain the observed phenotype (PMID: 32746448). This variant has not been identified 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at