RNF40
protein-codingring finger protein 40, the group of Ring finger proteins
Gene summary
The protein encoded by this gene contains a RING finger, a motif known to be involved in protein-protein and protein-DNA interactions. This protein was reported to interact with the tumor suppressor protein RB1. Studies of the rat counterpart suggested that this protein may function as an E3 ubiquitin-protein ligase, and facilitate the ubiquitination and degradation of syntaxin 1, which is an essential component of the neurotransmitter release machinery. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2011]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~14.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0005453
Submitter: ClinGen
*RNF40* was first reported in relation to autosomal dominant congenital heart disease in 2017 (Jin et al. 2017, PMID:28991257). Only one splice site variant reported in an individual with congenital heart disease was included in this curation (PMID: 28991257, 31235600). This gene-disease relationship is also supported by a MO knockdown of *rnf20/rnf40* in Xenopus which showed abnormal heart looping, defective development of left–right (LR) asymmetry, and impaired cilia motility (PMID: 31235600). In summary, there is limited evidence supporting the relationship between *RNF40* and autosomal dominant congenital heart disease. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date April 30th, 2024 (SOP Version 10).
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to RNF40 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_014771.4. 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 | 1 | 2 | 1 | 4 | ||
| missense | 115 | 2 | 117 | |||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 6 | 6 | ||||
| Total | 0 | 0 | 123 | 4 | 1 | 128 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_055586.1 | 19 | MANE Select | |
| Ensembl | ENSP00000325677.6 | 19 | MANE Select | |
| RefSeq | NP_001193962.1 | 19 | Standard | |
| RefSeq | NP_001193963.1 | 17 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- ATM Signaling Network in Development and Disease
- Post-translational protein modification
- Metabolism of proteins
- Protein ubiquitination
- E3 ubiquitin ligases ubiquitinate target proteins
Biological Process
- ubiquitin-dependent protein catabolic process
- regulation of mitotic cell cycle
- histone monoubiquitination
- protein ubiquitination
- histone H2B ubiquitination
Molecular Function
- mRNA 3'-UTR binding
- ubiquitin-protein transferase activity
- protein binding
- syntaxin-1 binding
- ubiquitin conjugating enzyme binding
Cellular Component
- ubiquitin ligase complex
- nucleus
- nucleoplasm
- cytosol
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000324685
- Coding exons
- 19
- Length
- 14563
- Individuals with no LoFs
- 125651
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 97
- Defined
- 125748
- p
- 0.000386
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.70 | 439 | 630 | 0.697 | 0.0000422 | 6435 |
| Missense (PolyPhen) | 62 | 156.21 | 0.3969 | 1712 | ||
| Synonymous | 1.18 | 223 | 247 | 0.904 | 0.0000144 | 2032 |
| Loss of Function | 6.27 | 8 | 60.8 | 0.132 | 0.00000395 | 608 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.00078 | 0.00076 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the RNF20/40 E3 ubiquitin-protein ligase complex that mediates monoubiquitination of 'Lys-120' of histone H2B (H2BK120ub1). H2BK120ub1 gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation (H3K4me and H3K79me, respectively). It thereby plays a central role in histone code and gene regulation. The RNF20/40 complex forms a H2B ubiquitin ligase complex in cooperation with the E2 enzyme UBE2A or UBE2B; reports about the cooperation with UBE2E1/UBCH are contradictory. Required for transcriptional activation of Hox genes. {ECO:0000269|PubMed:16307923, ECO:0000269|PubMed:19410543}.;
Recessive Scores
- pRec
- 0.176
Intolerance Scores
- LoFtool
- 0.457
- RVIS EVS
- -1.99
- RVIS percentile EVS
- 1.76
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.674
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |