RAB39B
protein-codingRAB39B, member RAS oncogene family, the group of RAB, member RAS oncogene GTPases
Gene summary
This gene encodes a member of the Rab family of proteins. Rab proteins are small GTPases that are involved in vesicular trafficking. Mutations in this gene are associated with X-linked cognitive disability. [provided by RefSeq, Aug 2013]
- MRX72
- WSN
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~6.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0010709
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010709
Submitter: ClinGen
*RAB39B* was first reported in relation to X-linked intellectual disability in 2010 (Giannandrea et al., PMID: 20159109) and was subsequently reported in relation to X-linked early-onset parkinsonism-intellectual disability syndrome in 2014 (Wilson et al., PMID: 25434005). *RAB39B* encodes a protein involved in vesicular trafficking. The disorder is characterized by intellectual disability, early-onset parkinsonism, macrocephaly, and seizures. Six variants (nonsense, frameshift, splice, and missense) that have been reported in 7 probands in 5 publications (PMIDs: 20159109, 21076407, 25434005, 27066548, 28851564) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by experimental evidence in mouse hippocampal neurons (PMIDs: 20159109, 25784538). In summary, there is definitive evidence supporting the relationship between *RAB39B* and X-linked early-onset parkinsonism-intellectual disability syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on June 4, 2018 (SOP Version 5). As of July 2022, this record underwent administrative updates to include an evidence summary text and update scoring to be consistent with SOP Version 9. No new evidence has been added.
Inheritance Pattern: XL
Disease ID:MONDO:0010289
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010709
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0019181
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010289
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0010709
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0010709
Submitter: Genomics England PanelApp
Inheritance Pattern: XL
Disease ID:MONDO:0010289
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0010709
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Neurologic
Intervention: Neurologic
Rationale: Waisman syndrome has been reported as being responsive to levodopa
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to RAB39B variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_171998.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 5 | 13 | 18 | |||
| missense | 2 | 1 | 55 | 2 | 60 | |
| nonsense | 3 | 3 | ||||
| start loss | 2 | 2 | ||||
| frameshift | 1 | 2 | 2 | 5 | ||
| splice donor/acceptor (+/-2bp) | 1 | 2 | 3 | |||
| Total | 9 | 3 | 64 | 15 | 0 | 91 |
Highest pathogenic variant AF is 9.1064396e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_741995.1 | 2 | MANE Select | |
| Ensembl | ENSP00000358466.3 | 2 | MANE Select | |
| Ensembl | ENSP00000809551.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Vesicle-mediated transport
- Membrane Trafficking
- Post-translational protein modification
- Metabolism of proteins
- Rab regulation of trafficking
Biological Process
- intracellular protein transport
- autophagy
- regulation of autophagy
- vesicle-mediated transport
- Rab protein signal transduction
Molecular Function
- GTPase activity
- protein binding
- GTP binding
- myosin V binding
Cellular Component
- Golgi apparatus
- plasma membrane
- cytoplasmic vesicle membrane
- vesicle
- neuron projection
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000369454
- Coding exons
- 2
- Length
- 6349
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.94 | 36 | 87.0 | 0.414 | 0.00000642 | 1383 |
| Missense (PolyPhen) | 7 | 40.003 | 0.17499 | 604 | ||
| Synonymous | 0.686 | 30 | 35.2 | 0.853 | 0.00000274 | 431 |
| Loss of Function | 2.22 | 0 | 5.76 | 0.00 | 4.38e-7 | 86 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Small GTPases Rab involved in autophagy (PubMed:27103069). The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion (PubMed:27103069). May regulate the homeostasis of SNCA/alpha-synuclein. Together with PICK1 proposed to ensure selectively GRIA2 exit from the endoplasmic reticulum to the Golgi and to regulate AMPAR compostion at the post-synapses and thus synaptic transmission (By similarity). {ECO:0000250|UniProtKB:Q8BHC1, ECO:0000269|PubMed:27103069}.;
- Disease
- DISEASE: Waisman syndrome (WSMN) [MIM:311510]: A neurologic disorder characterized by delayed psychomotor development, intellectual disability, and early-onset Parkinson disease. {ECO:0000269|PubMed:25434005, ECO:0000269|PubMed:26399558, ECO:0000269|PubMed:27066548}. Note=The disease is caused by mutations affecting the gene represented in this entry. Its association with Parkinson disease is however unclear (PubMed:26739247, PubMed:27459931). According to a number of studies, variations affecting this gene are not a frequent cause of Parkinson disease, suggesting that RAB39B does not play a major role in Parkinson disease etiology (PubMed:26739247, PubMed:27459931). {ECO:0000269|PubMed:26739247, ECO:0000269|PubMed:27459931}.;
Recessive Scores
- pRec
- 0.113
Intolerance Scores
- RVIS EVS
- 0.01
- RVIS percentile EVS
- 54.63
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.0314