RNF139
protein-codingring finger protein 139, the group of Ring finger proteins
Gene summary
The protein encoded by this gene is a multi-membrane spanning protein containing a RING-H2 finger. This protein is located in the endoplasmic reticulum, and has been shown to possess ubiquitin ligase activity. This gene was found to be interrupted by a t(3:8) translocation in a family with hereditary renal and non-medulary thyroid cancer. Studies of the Drosophila counterpart suggested that this protein may interact with tumor suppressor protein VHL, as well as with COPS5/JAB1, a protein responsible for the degradation of tumor suppressor CDKN1B/P27KIP. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~13.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: Unknown
Disease ID:MONDO:0007763
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007763
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Oncologic
Intervention: Oncologic
Rationale: Surveillance and early detection of and treatment for malignancy (a number of cancer types have been described, including renal cell cancer and dysgerminoma) may decrease morbidity and mortality
Comments: Genomic disruptions have been reported
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to RNF139 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_007218.4. 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 | 3 | 3 | ||||
| missense | 68 | 68 | ||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 68 | 3 | 0 | 71 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_009149.2 | 2 | MANE Select | |
| Ensembl | ENSP00000304051.4 | 2 | MANE Select | |
| Ensembl | ENSP00000429836.2 | 1 | Standard | |
| Ensembl | ENSP00000520565.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Sterol Regulatory Element-Binding Proteins (SREBP) signalling
- ER Quality Control Compartment (ERQC)
- Calnexin/calreticulin cycle
- Post-translational protein modification
- Metabolism of proteins
Biological Process
- negative regulation of cell population proliferation
- protein ubiquitination
- negative regulation of translation
- protein destabilization
- ERAD pathway
Molecular Function
- protease binding
- ubiquitin-protein transferase activity
- protein binding
- zinc ion binding
- ubiquitin-like protein transferase activity
Cellular Component
- endoplasmic reticulum
- endoplasmic reticulum membrane
- endomembrane system
- integral component of membrane
- Derlin-1 retrotranslocation complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000303545
- Coding exons
- 2
- Length
- 13177
- Individuals with no LoFs
- 125708
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 40
- Defined
- 125748
- p
- 0.000159
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.84 | 261 | 359 | 0.727 | 0.0000189 | 4338 |
| Missense (PolyPhen) | 57 | 108.17 | 0.52697 | 1354 | ||
| Synonymous | -0.887 | 150 | 137 | 1.10 | 0.00000713 | 1333 |
| Loss of Function | 3.59 | 5 | 24.0 | 0.208 | 0.00000147 | 285 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00038 | 0.00038 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.00028 | 0.00028 | rare |
| European (Non-Finnish) | 0.00012 | 0.00011 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: E3-ubiquitin ligase; acts as a negative regulator of the cell proliferation through mechanisms involving G2/M arrest and cell death. Required for MHC class I ubiquitination in cells expressing the cytomegalovirus protein US2 before dislocation from the endoplasmic reticulum (ER). Affects SREBP processing by hindering the SREBP/SCAP complex translocation from the ER to the Golgi, thereby reducing SREBF2 target gene expression. Required for INSIG1 ubiquitination. May be required for EIF3 complex ubiquitination. May function as a signaling receptor. {ECO:0000269|PubMed:10500182, ECO:0000269|PubMed:12032852, ECO:0000269|PubMed:17016439, ECO:0000269|PubMed:19706601, ECO:0000269|PubMed:19720873, ECO:0000269|PubMed:20068067}.;
- Disease
- DISEASE: Renal cell carcinoma (RCC) [MIM:144700]: Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into clear cell renal carcinoma (non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma. Clear cell renal cell carcinoma is the most common subtype. Note=The disease may be caused by mutations affecting the gene represented in this entry. A chromosomal aberration involving RNF139 has been found in a lymphoblastoid cell line established from a family with renal cell carcinoma and thyroid carcinoma. Translocation (3;8)(q14.2;q24.1) with FHIT. RNF139 is found to be fused to FHIT and disrupted within the sterol-sensing domain. In contrast, the FHIT coding region is maintained and expressed. Sporadic cases of renal carcinoma, where an acquired mutation in RNF139 results in the duplication of 12 nucleotides in the 5'-UTR, has also been identified.;
Recessive Scores
- pRec
- 0.115
Intolerance Scores
- LoFtool
- 0.463
- RVIS EVS
- -0.71
- RVIS percentile EVS
- 14.5
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.844
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |