FNIP1
protein-codingfolliculin interacting protein 1, the group of DENN domain containing
Gene summary
This gene encodes a protein that binds to the tumor suppressor protein folliculin and to AMP-activated protein kinase (AMPK). The encoded protein participates in the regulation of cellular metabolism and nutrient sensing by modulating the AMPK and target of rapamycin signaling pathways. This gene has a closely related paralog that encodes a protein with similar binding activities. Both related proteins also associate with the molecular chaperone heat shock protein-90 (Hsp90) and negatively regulate its ATPase activity and facilitate its association with folliculin. [provided by RefSeq, Jul 2017]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~155.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0030528
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0030528
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0100432
Submitter: ClinGen
*FNIP1* was first reported in relation to autosomal recessive *FNIP1*-associated syndrome in 2020 (Niehues T, et al., 2020, PMID: 32181500). Folliculin interacting protein 1 (*FNIP1*) encodes the FNIP1 protein, a regulator of adenosine monophosphate-activated protein (AMPK) and mammalian target of rapamycin (mTOR) cellular pathways. FNIP1 controls B cell development through regulation of mitochondrial autophagy (reviewed in PMID: 39013219). FNIP1 deficiency is associated with a syndromic disease that includes B cell immunodeficiency and cardiomyopathy. The latter is related to the important role of FNIP1 in controlling skeletal muscle functional angiogenesis, which is required for muscle revascularization during ischemia (PMID: 37932296). Seven variants (missense, nonsense, frameshift, and splice site) have been reported in seven probands, and one additional family member, in four publications (PMIDs: 32181500, 32905580, 37522988, 39537849). This gene-disease association is supported by its function in nutrient/energy sensing (PMID: 17028174), which is altered in patient cells (PMID: 32905580). Additionally, mouse models recapitulate the block at the pre-B-cell stage and dysregulation of metabolic regulators (PMIDs: 22608497, 22709692) as well as some key features of the disease (PMID: 27303042). In summary, there is definitive evidence to support the relationship between *FNIP1* and autosomal recessive *FNIP1*-associated syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the Antibody Deficiencies GCEP on November, 16 2021. It was reevaluated on November 22, 2024. As a result of this reevaluation, the classification changed from Strong to Definitive due to the replication of this gene-disease relationship over time and two additional case reports (PMIDs: 37522988, 39537849).
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Cardiovascular
Intervention: Allergy/Immunology/Infectious; Cardiovascular
Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; The condition can involve structural and other cardiovascular anoamalies, and awareness may allow early diagnosis and management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FNIP1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_133372.3. 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 | 138 | 9 | 148 | ||
| missense | 1 | 1 | 189 | 14 | 3 | 208 |
| nonsense | 7 | 1 | 8 | |||
| start loss | 0 | |||||
| frameshift | 12 | 1 | 13 | |||
| splice donor/acceptor (+/-2bp) | 1 | 2 | 4 | 7 | ||
| Total | 21 | 3 | 196 | 152 | 12 | 384 |
Highest pathogenic variant AF is 0.000004796939
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_588613.3 | 18 | MANE Select | |
| Ensembl | ENSP00000421985.1 | 18 | MANE Select | |
| RefSeq | NP_001008738.3 | 17 | Standard | |
| RefSeq | NP_001333042.2 | 13 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- mTOR signaling pathway - Homo sapiens (human)
Biological Process
- negative regulation of transcription by RNA polymerase II
- regulation of protein phosphorylation
- positive regulation of protein phosphorylation
- immature B cell differentiation
- positive regulation of B cell apoptotic process
Molecular Function
- guanyl-nucleotide exchange factor activity
- protein binding
- ATPase inhibitor activity
- chaperone binding
Cellular Component
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000510461
- Coding exons
- 18
- Length
- 155304
- Individuals with no LoFs
- 125733
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 14
- Defined
- 125747
- p
- 0.0000557
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.35 | 449 | 613 | 0.733 | 0.0000312 | 7731 |
| Missense (PolyPhen) | 229 | 356.49 | 0.64237 | 4334 | ||
| Synonymous | 0.791 | 195 | 210 | 0.931 | 0.0000102 | 2156 |
| Loss of Function | 6.05 | 8 | 57.6 | 0.139 | 0.00000339 | 676 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00019 | 0.00018 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.00019 | 0.00018 | rare |
| European (Non-Finnish) | 0.000045 | 0.000044 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Acts as a co-chaperone of HSP90AA1. Inhibits the ATPase activity of HSP90AA1 leading to reduction in its chaperone activity. Facilitates the binding of client protein FLCN to HSP90AA1. Competes with the activating co-chaperone AHSA1 for binding to HSP90AA1, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins (PubMed:27353360). May be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways (PubMed:17028174). May regulate phosphorylation of RPS6KB1 (PubMed:18663353). {ECO:0000269|PubMed:17028174, ECO:0000269|PubMed:18663353, ECO:0000269|PubMed:27353360}.;
Intolerance Scores
- LoFtool
- 0.431
- RVIS EVS
- -0.57
- RVIS percentile EVS
- 19.01
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.867
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |