rs148147581
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_004415.4(DSP):c.1696G>A(p.Ala566Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000303 in 1,612,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A566A) has been classified as Likely benign.
Frequency
Consequence
NM_004415.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.1696G>A | p.Ala566Thr | missense_variant | 13/24 | ENST00000379802.8 | |
DSP | NM_001319034.2 | c.1696G>A | p.Ala566Thr | missense_variant | 13/24 | ||
DSP | NM_001008844.3 | c.1696G>A | p.Ala566Thr | missense_variant | 13/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.1696G>A | p.Ala566Thr | missense_variant | 13/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.1696G>A | p.Ala566Thr | missense_variant | 13/24 | 1 | A2 | ||
DSP | ENST00000710359.1 | c.1696G>A | p.Ala566Thr | missense_variant | 13/24 | A2 | |||
DSP | ENST00000684395.1 | n.80G>A | non_coding_transcript_exon_variant | 1/5 |
Frequencies
GnomAD3 genomes ? AF: 0.000263 AC: 40AN: 152144Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000199 AC: 50AN: 251036Hom.: 0 AF XY: 0.000221 AC XY: 30AN XY: 135668
GnomAD4 exome AF: 0.000307 AC: 448AN: 1460666Hom.: 0 Cov.: 32 AF XY: 0.000307 AC XY: 223AN XY: 726638
GnomAD4 genome ? AF: 0.000263 AC: 40AN: 152262Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21AN XY: 74450
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:3
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 08, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 16, 2021 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 04, 2020 | Published in association with ARVC (Basso et al., 2006; Cox et al., 2011; Cann et al., 2016), HCM (Lopes et al., 2015), and DCM (Franaszczyk et al., 2017) and found to independently segregate with disease in a relative of a proband with ARVC (Cann et al., 2016); Identified in individuals referred for cardiac genetic testing at GeneDx; however, some of these probands harbored pathogenic variants in other cardiomyopathy-related genes, and segregation data are limited at this time; Reported in ClinVar (ClinVar Variant ID# 161226; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Functional studies suggest that the A566T variant alone is insufficient to impair protein function (Patel et al., 2014); This variant is associated with the following publications: (PMID: 25637381, 24055113, 25225338, 16774985, 21606396, 23299917, 26332594, 25351510, 28045975, 27000522, 26606670, 31402444) - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Arrhythmogenic right ventricular dysplasia 8 Uncertain:1Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | Jun 18, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 31, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
not specified Benign:2
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 05, 2017 | p.Ala566Thr in exon 13 of DSP: This variant is not expected to have clinical sig nificance because it has been identified in 0.03% (40/126324) of European chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute .org; dbSNP ${MatchVariant_1_dbSNPrsNumber}). ACMG/AMP Criteria applied: BS1. - |
Arrhythmogenic right ventricular cardiomyopathy Uncertain:1
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Skin fragility with non-scarring blistering;C4024876:Palmoplantar blistering Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
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
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 23, 2017 | - - |
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 19, 2024 | - - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 13, 2019 | - - |
Lethal acantholytic epidermolysis bullosa Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 31, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Woolly hair-skin fragility syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 31, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 28, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Uncertain significance and reported on 12-28-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at