SIAH2
protein-codingsiah E3 ubiquitin protein ligase 2, the group of Ring finger proteins
Gene summary
This gene encodes a protein that is a member of the seven in absentia homolog (SIAH) family. The protein is an E3 ligase and is involved in ubiquitination and proteasome-mediated degradation of specific proteins. The activity of this ubiquitin ligase has been implicated in regulating cellular response to hypoxia. [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 ~22.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SIAH2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005067.7. 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 | 2 | 2 | ||||
| missense | 30 | 30 | ||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 30 | 0 | 2 | 32 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005058.3 | 2 | MANE Select | |
| Ensembl | ENSP00000322457.3 | 2 | MANE Select | |
| Ensembl | ENSP00000417619.1 | 2 | Standard | |
| Ensembl | ENSP00000606617.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Parkin-Ubiquitin Proteasomal System pathway
- Endoderm Differentiation
- Developmental Biology
- Post-translational protein modification
- Metabolism of proteins
Biological Process
- protein polyubiquitination
- ubiquitin-dependent protein catabolic process
- apoptotic process
- cell cycle
- small GTPase mediated signal transduction
Molecular Function
- transcription corepressor activity
- ubiquitin-protein transferase activity
- protein binding
- zinc ion binding
- ubiquitin conjugating enzyme binding
Cellular Component
- nucleoplasm
- cytoplasm
- early endosome
- cytosol
- neuron projection
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000312960
- Coding exons
- 2
- Length
- 22351
- Individuals with no LoFs
- 125746
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 125748
- p
- 0.00000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.43 | 81 | 170 | 0.476 | 0.00000940 | 2094 |
| Missense (PolyPhen) | 17 | 66.78 | 0.25457 | 791 | ||
| Synonymous | 0.229 | 72 | 74.5 | 0.966 | 0.00000444 | 681 |
| Loss of Function | 2.31 | 1 | 8.09 | 0.124 | 3.44e-7 | 103 |
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) | 0.000018 | 0.000018 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin- conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Mediates E3 ubiquitin ligase activity either through direct binding to substrates or by functioning as the essential RING domain subunit of larger E3 complexes. Triggers the ubiquitin-mediated degradation of many substrates, including proteins involved in transcription regulation (GPS2, POU2AF1, PML, NCOR1), a cell surface receptor (DCC), an antiapoptotic protein (BAG1), and a protein involved in synaptic vesicle function in neurons (SYP). Mediates ubiquitination and proteasomal degradation of DYRK2 in response to hypoxia. It is thereby involved in apoptosis, tumor suppression, cell cycle, transcription and signaling processes. Has some overlapping function with SIAH1. Triggers the ubiquitin- mediated degradation of TRAF2, whereas SIAH1 does not. Promotes monoubiquitination of SNCA. {ECO:0000269|PubMed:11483518, ECO:0000269|PubMed:12411493, ECO:0000269|PubMed:19224863, ECO:0000269|PubMed:22878263, ECO:0000269|PubMed:9334332}.;
Recessive Scores
- pRec
- 0.203
Intolerance Scores
- LoFtool
- 0.0751
- RVIS EVS
- -0.16
- RVIS percentile EVS
- 41.25
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.942
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |