TRIM8
protein-codingtripartite motif containing 8, the group of Tripartite motif family|Ring finger proteins
Gene summary
This gene encodes a member of the tripartite motif (TRIM) protein family. Based on similarities to other proteins, the encoded protein is suspected to be an E3 ubiquitin-protein ligase. Regulation of this gene may be altered in some cancers. Mutations resulting in a truncated protein product have been observed in early-onset epileptic encephalopathy (EOEE). [provided by RefSeq, Sep 2016]
- RNF27
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~20.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0100111
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0100111
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0100111
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0100062
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0100111
Submitter: ClinGen
*TRIM8* encodes an E3 ubiquitin ligase. Although *TRIM8* variants were initially observed in cases of epileptic encephalopathy in 2013 and 2016 (PMIDs: 23934111, 27346735), the first report focusing on variants in *TRIM8* as a cause of autosomal dominant focal segmental glomerulosclerosis and neurodevelopmental syndrome (FSGSNEDS) was published in 2018 (PMID: 30244534). To date, *de novo TRIM8* variants have been reported in at least 20 individuals with FSGSNEDS (PMIDs: 23934111, 27346735, 30244534, 32193649, 32531461, 33508234). FSGSNEDS results in early-onset developmental delay (DD) and mild to severe intellectual disability in all reported patients, seizures in 19/20 reported patients, and renal manifestations (proteinuria, steroid resistant nephrotic syndrome, focal segmental glomerulosclerosis, diffuse mesangial sclerosis) in 17/20 reported patients (PMIDs: 30244534, 33508234). The reported renal manifestations may not present until later in childhood or adolescence (PMID: 33508234). To date, all reported *TRIM8* variants observed in individuals with FSGSNEDS have been *de novo* nonsense or frameshift variants that cluster within the last exon between residues 390 and 487; these variants are expected to escape nonsense mediated decay and are hypothesized to act through gain-of-function or toxic effects (PMID: 33508234). In addition, *TRIM8* constructs carrying patient-specific variants mislocalized to the nucleoplasm instead of nuclear bodies in podocytes and neuronal cells (PMID: 33508234). In summary, the *TRIM8* gene is definitively associated with autosomal dominant focal segmental glomerulosclerosis and neurodevelopmental syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 6 2021 (SOP Version 8).
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; Renal
Intervention: Renal
Rationale: Among other features, the condition can include renal disease, and awareness may allow early diagnosis and management
Comments: Renal transplant has been described
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TRIM8 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_030912.3. 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 | 1 | 147 | 2 | 150 | ||
| missense | 186 | 62 | 5 | 253 | ||
| nonsense | 11 | 8 | 5 | 24 | ||
| start loss | 2 | 2 | ||||
| frameshift | 2 | 8 | 7 | 17 | ||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 13 | 16 | 205 | 209 | 7 | 450 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_112174.2 | 6 | MANE Select | |
| Ensembl | ENSP00000496301.1 | 6 | MANE Select | |
| RefSeq | NP_001332879.1 | 5 | Standard | |
| Ensembl | ENSP00000302120.6 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cytokine Signaling in Immune system
- Immune System
- Interferon gamma signaling
- Interferon Signaling
Biological Process
- positive regulation of autophagy
- protein ubiquitination
- stem cell population maintenance
- negative regulation of viral transcription
- positive regulation of I-kappaB kinase/NF-kappaB signaling
Molecular Function
- protein binding
- zinc ion binding
- transferase activity
- identical protein binding
- protein homodimerization activity
Cellular Component
- cytosol
- PML body
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000302424
- Coding exons
- 6
- Length
- 13912
- Individuals with no LoFs
- 125742
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 6
- Defined
- 125748
- p
- 0.0000239
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.74 | 198 | 340 | 0.582 | 0.0000201 | 3574 |
| Missense (PolyPhen) | 38 | 95.399 | 0.39833 | 1116 | ||
| Synonymous | 1.42 | 139 | 162 | 0.858 | 0.0000109 | 1082 |
| Loss of Function | 4.18 | 2 | 24.2 | 0.0826 | 0.00000113 | 259 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000029 | 0.000026 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: E3 ubiquitin-protein ligase which plays different roles in immune pathways. Participates in the activation of interferon- gamma signaling by promoting proteasomal degradation of the repressor SOCS1 (PubMed:12163497). Plays a positive role in the TNFalpha and IL-1beta signaling pathways. Mechanistically, induces the 'lys-63' polyubiquitination of MAP3K7/TAK1 component leading to the activation of NF-kappa-B (PubMed:22084099, PubMed:23152791). Modulates also STAT3 activity through negative regulation of PIAS3, either by degradation of PIAS3 through the ubiquitin-proteasome pathway or exclusion of PIAS3 from the nucleus (PubMed:20516148). {ECO:0000269|PubMed:12163497, ECO:0000269|PubMed:20516148, ECO:0000269|PubMed:22084099, ECO:0000269|PubMed:23152791}.;
Recessive Scores
- pRec
- 0.125
Intolerance Scores
- RVIS EVS
- -0.56
- RVIS percentile EVS
- 19.31
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.776
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |