VPS35
Basic information
Region (hg38): 16:46656132-46689518
Links
Phenotypes
GenCC
Source:
- Parkinson disease 17 (Strong), mode of inheritance: AD
- hereditary late onset Parkinson disease (Supportive), mode of inheritance: AD
- Parkinson disease 17 (Moderate), mode of inheritance: AD
- intellectual disability (Limited), mode of inheritance: AR
- Parkinson disease 17 (Strong), mode of inheritance: AD
- Parkinson disease (Definitive), mode of inheritance: AD
Clinical Genomic Database
Source:
Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
---|---|---|---|---|---|
Parkinson disease 17 | AD | Neurologic | Individuals have been described with levodopa response | Neurologic | 18342564; 21763482; 21763483; 22517097; 23408866; 23623008 |
ClinVar
This is a list of variants' phenotypes submitted to
- not provided (1 variants)
- Parkinson disease 17 (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the VPS35 gene is commonly pathogenic or not.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
---|---|---|---|---|---|---|
synonymous | 33 | 37 | ||||
missense | 69 | 75 | ||||
nonsense | 2 | |||||
start loss | 0 | |||||
frameshift | 0 | |||||
inframe indel | 0 | |||||
splice donor/acceptor (+/-2bp) | 0 | |||||
splice region | 3 | 4 | 2 | 9 | ||
non coding | 26 | 40 | 20 | 86 | ||
Total | 1 | 1 | 99 | 76 | 23 |
Variants in VPS35
This is a list of pathogenic ClinVar variants found in the VPS35 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
Position | Type | Phenotype | Significance | ClinVar |
---|---|---|---|---|
16-46659709-C-CA | Parkinson Disease, Dominant | Likely benign (Jun 14, 2016) | ||
16-46659709-C-CAA | Parkinson Disease, Dominant | Uncertain significance (Jun 14, 2016) | ||
16-46659855-T-C | Parkinson disease 17 | Uncertain significance (Jan 13, 2018) | ||
16-46659897-T-A | Parkinson disease 17 | Uncertain significance (Jan 12, 2018) | ||
16-46660050-G-T | Parkinson disease 17 | Benign (Jan 13, 2018) | ||
16-46660071-C-T | Parkinson disease 17 | Uncertain significance (Jan 12, 2018) | ||
16-46660092-C-T | Parkinson disease 17 | Uncertain significance (Jan 13, 2018) | ||
16-46660118-C-G | Parkinson disease 17 | Benign (Jan 13, 2018) | ||
16-46660126-C-T | Parkinson disease 17 | Benign (Jan 13, 2018) | ||
16-46660127-A-C | Parkinson disease 17 | Uncertain significance (Jan 13, 2018) | ||
16-46660183-G-A | Parkinson disease 17 | Likely benign (Jan 12, 2018) | ||
16-46660184-G-GT | Parkinson Disease, Dominant | Uncertain significance (Jun 14, 2016) | ||
16-46660184-G-GGTT | Parkinson Disease, Dominant | Uncertain significance (Jun 14, 2016) | ||
16-46660184-G-GTTT | Parkinson Disease, Dominant | Uncertain significance (Jun 14, 2016) | ||
16-46660184-G-GGTTT | Parkinson Disease, Dominant | Uncertain significance (Jun 14, 2016) | ||
16-46660187-TTG-T | Parkinson Disease, Dominant | Uncertain significance (Jun 14, 2016) | ||
16-46660188-TG-T | Parkinson Disease, Dominant | Conflicting classifications of pathogenicity (Sep 02, 2019) | ||
16-46660189-G-T | Parkinson disease 17 | Uncertain significance (Jan 13, 2018) | ||
16-46660189-G-GTTTTTT | Likely benign (Mar 01, 2023) | |||
16-46660189-G-GTTTTTTT | Benign (Aug 01, 2022) | |||
16-46660191-G-TTTT | Parkinson Disease, Dominant | Uncertain significance (Jun 14, 2016) | ||
16-46660191-G-TTTTT | Parkinson Disease, Dominant | Uncertain significance (Jun 14, 2016) | ||
16-46660192-T-TTTTG | Parkinson Disease, Dominant | Uncertain significance (Jun 14, 2016) | ||
16-46660193-T-TTTG | Parkinson Disease, Dominant | Uncertain significance (Jun 14, 2016) | ||
16-46660194-T-TTG | Parkinson Disease, Dominant | Uncertain significance (Jun 14, 2016) |
GnomAD
Source:
Gene | Type | Bio Type | Transcript | Coding Exons | Length |
---|---|---|---|---|---|
VPS35 | protein_coding | protein_coding | ENST00000299138 | 17 | 33377 |
pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
---|---|---|---|---|---|---|
0.969 | 0.0308 | 125717 | 0 | 30 | 125747 | 0.000119 |
Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
---|---|---|---|---|---|---|
Missense | 3.53 | 220 | 425 | 0.518 | 0.0000220 | 5274 |
Missense in Polyphen | 41 | 140.16 | 0.29253 | 1834 | ||
Synonymous | 0.261 | 141 | 145 | 0.972 | 0.00000720 | 1464 |
Loss of Function | 5.20 | 8 | 46.0 | 0.174 | 0.00000261 | 522 |
LoF frequencies by population
Ethnicity | Sum of pLOFs | p |
---|---|---|
African & African-American | 0.000347 | 0.000347 |
Ashkenazi Jewish | 0.00 | 0.00 |
East Asian | 0.00 | 0.00 |
Finnish | 0.0000924 | 0.0000924 |
European (Non-Finnish) | 0.000132 | 0.000132 |
Middle Eastern | 0.00 | 0.00 |
South Asian | 0.00 | 0.00 |
Other | 0.000163 | 0.000163 |
dbNSFP
Source:
- Function
- FUNCTION: Acts as component of the retromer cargo-selective complex (CSC). The CSC is believed to be the core functional component of retromer or respective retromer complex variants acting to prevent missorting of selected transmembrane cargo proteins into the lysosomal degradation pathway. The recruitment of the CSC to the endosomal membrane involves RAB7A and SNX3. The CSC seems to associate with the cytoplasmic domain of cargo proteins predominantly via VPS35; however, these interactions seem to be of low affinity and retromer SNX proteins may also contribute to cargo selectivity thus questioning the classical function of the CSC. The SNX-BAR retromer mediates retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN) and is involved in endosome-to-plasma membrane transport for cargo protein recycling. The SNX3-retromer mediates the retrograde endosome-to-TGN transport of WLS distinct from the SNX-BAR retromer pathway. The SNX27-retromer is believed to be involved in endosome-to-plasma membrane trafficking and recycling of a broad spectrum of cargo proteins. The CSC seems to act as recruitment hub for other proteins, such as the WASH complex and TBC1D5 (Probable). Required for retrograde transport of lysosomal enzyme receptor IGF2R and SLC11A2. Required to regulate transcytosis of the polymeric immunoglobulin receptor (pIgR-pIgA) (PubMed:15078903, PubMed:15247922, PubMed:20164305). Required for endosomal localization of WASHC2C (PubMed:22070227). Mediates the association of the CSC with the WASH complex via WASHC2 (PubMed:22070227, PubMed:24980502, PubMed:24819384). Required for the endosomal localization of TBC1D5 (PubMed:20923837). {ECO:0000269|PubMed:15078903, ECO:0000269|PubMed:15247922, ECO:0000269|PubMed:20164305, ECO:0000269|PubMed:20923837, ECO:0000269|PubMed:22070227, ECO:0000269|PubMed:23395371, ECO:0000269|PubMed:24819384, ECO:0000269|PubMed:24980502, ECO:0000303|PubMed:21725319, ECO:0000303|PubMed:22070227, ECO:0000303|PubMed:22513087, ECO:0000303|PubMed:23563491}.;
- Pathway
- Endocytosis - Homo sapiens (human);Signaling by WNT;Signal Transduction;WNT ligand biogenesis and trafficking
(Consensus)
Recessive Scores
- pRec
- 0.203
Intolerance Scores
- loftool
- 0.406
- rvis_EVS
- -0.69
- rvis_percentile_EVS
- 15.12
Haploinsufficiency Scores
- pHI
- 0.519
- hipred
- Y
- hipred_score
- 0.749
- ghis
- 0.616
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- S
- essential_gene_gene_trap
- E
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.945
Gene Damage Prediction
All | Recessive | Dominant | |
---|---|---|---|
Mendelian | Medium | Medium | Medium |
Primary Immunodeficiency | Medium | Medium | Medium |
Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Vps35
- Phenotype
- normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; cellular phenotype; homeostasis/metabolism phenotype;
Gene ontology
- Biological process
- intracellular protein transport;lysosome organization;synapse assembly;positive regulation of gene expression;negative regulation of gene expression;regulation of mitochondrion organization;viral process;Wnt signaling pathway;regulation of macroautophagy;regulation of protein stability;protein destabilization;regulation of cellular protein metabolic process;negative regulation of protein homooligomerization;protein localization to organelle;retrograde transport, endosome to Golgi;mitochondrial fragmentation involved in apoptotic process;transcytosis;negative regulation of inflammatory response;voluntary musculoskeletal movement;positive regulation of dopamine receptor signaling pathway;negative regulation of cell death;positive regulation of Wnt protein secretion;positive regulation of mitochondrial fission;positive regulation of canonical Wnt signaling pathway;positive regulation of locomotion involved in locomotory behavior;neurotransmitter receptor transport, endosome to postsynaptic membrane;vesicle-mediated transport in synapse;mitochondrion to lysosome transport;neurotransmitter receptor transport, endosome to plasma membrane;negative regulation of neuron death;negative regulation of late endosome to lysosome transport;regulation of dendritic spine maintenance;positive regulation of dopamine biosynthetic process;positive regulation of cellular protein catabolic process;negative regulation of cellular protein localization;negative regulation of lysosomal protein catabolic process;regulation of presynapse assembly;retrograde transport, endosome to plasma membrane;regulation of terminal button organization
- Cellular component
- mitochondrion;lysosome;lysosomal membrane;endosome;early endosome;late endosome;cytosol;plasma membrane;endosome membrane;postsynaptic density;retromer complex;retromer, cargo-selective complex;neuron projection;neuronal cell body;perinuclear region of cytoplasm;extracellular exosome;tubular endosome;presynapse;glutamatergic synapse;mitochondrion-derived vesicle
- Molecular function
- protein binding;protein transporter activity;D1 dopamine receptor binding