rs147315869
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_004415.4(DSP):c.688G>A(p.Asp230Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000299 in 1,614,036 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00035 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00029 ( 2 hom. )
Consequence
DSP
NM_004415.4 missense
NM_004415.4 missense
Scores
2
7
10
Clinical Significance
Conservation
PhyloP100: 6.01
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 -8 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.013350904).
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.688G>A | p.Asp230Asn | missense_variant | 5/24 | ENST00000379802.8 | NP_004406.2 | |
DSP | NM_001319034.2 | c.688G>A | p.Asp230Asn | missense_variant | 5/24 | NP_001305963.1 | ||
DSP | NM_001008844.3 | c.688G>A | p.Asp230Asn | missense_variant | 5/24 | NP_001008844.1 | ||
DSP | NM_001406591.1 | c.688G>A | p.Asp230Asn | missense_variant | 5/11 | NP_001393520.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.688G>A | p.Asp230Asn | missense_variant | 5/24 | 1 | NM_004415.4 | ENSP00000369129.3 | ||
DSP | ENST00000418664.2 | c.688G>A | p.Asp230Asn | missense_variant | 5/24 | 1 | ENSP00000396591.2 | |||
DSP | ENST00000710359.1 | c.688G>A | p.Asp230Asn | missense_variant | 5/24 | ENSP00000518230.1 | ||||
DSP | ENST00000506617.1 | n.206G>A | non_coding_transcript_exon_variant | 2/4 | 3 |
Frequencies
GnomAD3 genomes AF: 0.000355 AC: 54AN: 152198Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000537 AC: 135AN: 251444Hom.: 2 AF XY: 0.000500 AC XY: 68AN XY: 135894
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GnomAD4 exome AF: 0.000293 AC: 428AN: 1461838Hom.: 2 Cov.: 31 AF XY: 0.000286 AC XY: 208AN XY: 727224
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GnomAD4 genome AF: 0.000355 AC: 54AN: 152198Hom.: 1 Cov.: 32 AF XY: 0.000323 AC XY: 24AN XY: 74342
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:9
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 22, 2019 | This variant is associated with the following publications: (PMID: 23299917, 23861362, 25351510, 20152563, 27153395, 29802319, 31402444) - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | DSP: BS1, BS2 - |
Cardiomyopathy Benign:2
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 12, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 13, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 20, 2016 | Variant classified as Uncertain Significance - Favor Benign. The p.Asp230Asn var iant in DSP has been reported in one adult with ARVC (Xu 2010) and two adults wi th HCM (LMM unpublished data). This variant has been identified in 48/66740 Eur opean chromosomes, including 1 homozygote, by the Exome Aggregation Consortium ( ExAC, http://exac.broadinstitute.org dbSNP rs147315869). Computational predictio n tools and conservation analysis do not provide strong support for or against a n impact to the protein. In summary, while the clinical significance of the p.As p230Asn variant is uncertain, its frequency suggests that it is more likely to be benign. - |
Arrhythmogenic right ventricular dysplasia 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 23, 2024 | - - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 05, 2017 | 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. - |
DSP-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 06, 2024 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
M;M
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;T
Polyphen
B;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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