rs199795359
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_004415.4(DSP):āc.3646A>Gā(p.Ile1216Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000353 in 1,614,176 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).
Frequency
Genomes: š 0.00012 ( 0 hom., cov: 32)
Exomes š: 0.000027 ( 0 hom. )
Consequence
DSP
NM_004415.4 missense
NM_004415.4 missense
Scores
1
18
Clinical Significance
Conservation
PhyloP100: 4.24
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 Likely_benign. Variant got -5 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0068103075).
BP6
?
Variant 6-7579836-A-G is Benign according to our data. Variant chr6-7579836-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44894.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.3646A>G | p.Ile1216Val | missense_variant | 23/24 | ENST00000379802.8 | |
DSP | NM_001319034.2 | c.3646A>G | p.Ile1216Val | missense_variant | 23/24 | ||
DSP | NM_001008844.3 | c.3582+64A>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.3646A>G | p.Ile1216Val | missense_variant | 23/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.3582+64A>G | intron_variant | 1 | A2 | ||||
DSP | ENST00000710359.1 | c.3646A>G | p.Ile1216Val | missense_variant | 23/24 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.000118 AC: 18AN: 152192Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000203 AC: 51AN: 251176Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135792
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GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461866Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 20AN XY: 727234
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GnomAD4 genome ? AF: 0.000118 AC: 18AN: 152310Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74470
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 01, 2008 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 08, 2013 | p.Ile1216Val (ATT>GTT): c.3646 A>G in exon 23 of the DSP gene (NM_004415.2). The Ile1216Val variant in the DSP gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Ile1216Val results in a conservative amino acid substitution of one non-polar amino acid for another, this substitution occurs at a position that is conserved across species. The Ile1216Val variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, Ile1216Val was observed in 0.4% of Asian alleles in the 1000 Genomes database. In silico algorithms are not consistent in their predictions but at least two concur that Ile1216Val is benign to the protein structure/function. In addition, mutations in nearby residues have not been reported (van der Zwaag P et al., 2009) indicating this region of the protein may tolerate change. With the clinical and molecular information available at this time, we cannot definitively determine if Ile1216Val is a disease-causing mutation or a rare benign variant. The variant is found in ARVC panel(s). - |
Cardiomyopathy Benign:2
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 03, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 05, 2018 | - - |
not provided Uncertain:1
Uncertain significance, 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
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 10, 2018 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
N
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
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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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at