rs80325569
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_004415.4(DSP):c.2815G>A(p.Gly939Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00209 in 1,613,254 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G939G) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.011 ( 29 hom., cov: 33)
Exomes 𝑓: 0.0011 ( 33 hom. )
Consequence
DSP
NM_004415.4 missense
NM_004415.4 missense
Scores
4
14
Clinical Significance
Conservation
PhyloP100: 3.83
Genes affected
DSP (HGNC:3052): (desmoplakin) This gene encodes a protein that anchors intermediate filaments to desmosomal plaques and forms an obligate component of functional desmosomes. Mutations in this gene are the cause of several cardiomyopathies and keratodermas, including skin fragility-woolly hair syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.00688228).
BP6
?
Variant 6-7576980-G-A is Benign according to our data. Variant chr6-7576980-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 36020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7576980-G-A is described in Lovd as [Benign]. Variant chr6-7576980-G-A is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0113 (1722/152212) while in subpopulation AFR AF= 0.0397 (1647/41518). AF 95% confidence interval is 0.0381. There are 29 homozygotes in gnomad4. There are 825 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 29 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.2815G>A | p.Gly939Ser | missense_variant | 20/24 | ENST00000379802.8 | |
DSP | NM_001319034.2 | c.2815G>A | p.Gly939Ser | missense_variant | 20/24 | ||
DSP | NM_001008844.3 | c.2815G>A | p.Gly939Ser | missense_variant | 20/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.2815G>A | p.Gly939Ser | missense_variant | 20/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.2815G>A | p.Gly939Ser | missense_variant | 20/24 | 1 | A2 | ||
DSP | ENST00000710359.1 | c.2815G>A | p.Gly939Ser | missense_variant | 20/24 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0113 AC: 1715AN: 152094Hom.: 29 Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00289 AC: 725AN: 251034Hom.: 13 AF XY: 0.00217 AC XY: 295AN XY: 135688
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GnomAD4 exome AF: 0.00113 AC: 1652AN: 1461042Hom.: 33 Cov.: 30 AF XY: 0.000965 AC XY: 701AN XY: 726718
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GnomAD4 genome ? AF: 0.0113 AC: 1722AN: 152212Hom.: 29 Cov.: 33 AF XY: 0.0111 AC XY: 825AN XY: 74406
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ESP6500AA
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Asia WGS
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:22
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:7
Benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jan 11, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 08, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 28, 2018 | This variant is associated with the following publications: (PMID: 25985138, 26332594, 27153395, 27884173, 20400443, 23299917, 20716751) - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 22, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | DSP: BP4, BS1, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
not specified Benign:5
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 07, 2012 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Cardiomyopathy Benign:3
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 04, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 19, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Cohesion Phenomics | Sep 23, 2022 | - - |
Arrhythmogenic right ventricular cardiomyopathy Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Feb 05, 2015 | - - |
Benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Lethal acantholytic epidermolysis bullosa Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 30, 2018 | 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 | Aug 30, 2018 | 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. - |
Arrhythmogenic right ventricular dysplasia 8 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 30, 2018 | 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. - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 01, 2015 | This alteration is classified as 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at