FHIT
protein-codingfragile histidine triad diadenosine triphosphatase, the group of MicroRNA protein coding host genes|Histidine triad superfamily
Gene summary
The protein encoded by this gene is a P1-P3-bis(5'-adenosyl) triphosphate hydrolase involved in purine metabolism. This gene encompasses the common fragile site FRA3B on chromosome 3, where carcinogen-induced damage can lead to translocations and aberrant transcripts. In fact, aberrant transcripts from this gene have been found in about half of all esophageal, stomach, and colon carcinomas. The encoded protein is also a tumor suppressor, as loss of its activity results in replication stress and DNA damage. [provided by RefSeq, Aug 2017]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~1,504.2 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 FHIT variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002012.4. 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 | 2 | 1 | 3 | |||
| missense | 28 | 3 | 31 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 3 | 3 | ||||
| Total | 0 | 0 | 31 | 5 | 1 | 37 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002003.1 | 5 | MANE Select | |
| Ensembl | ENSP00000418582.1 | 5 | MANE Select | |
| RefSeq | NP_001159715.1 | 5 | Standard | |
| RefSeq | NP_001307828.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Non-small cell lung cancer - Homo sapiens (human)
- Small cell lung cancer - Homo sapiens (human)
- Purine metabolism - Homo sapiens (human)
Biological Process
- purine nucleotide metabolic process
- nucleotide metabolic process
- negative regulation of proteasomal ubiquitin-dependent protein catabolic process
- intrinsic apoptotic signaling pathway by p53 class mediator
Molecular Function
- nucleotide binding
- catalytic activity
- protein binding
- hydrolase activity
- ubiquitin protein ligase binding
Cellular Component
- fibrillar center
- cytoplasm
- mitochondrion
- cytosol
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000468189
- Coding exons
- 5
- Length
- 1502098
- Individuals with no LoFs
- 125719
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 23
- Defined
- 125742
- p
- 0.0000915
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -1.06 | 120 | 91.4 | 1.31 | 0.00000557 | 964 |
| Missense (PolyPhen) | 45 | 30.796 | 1.4612 | 322 | ||
| Synonymous | -1.20 | 43 | 34.1 | 1.26 | 0.00000213 | 284 |
| Loss of Function | 0.813 | 4 | 6.18 | 0.647 | 2.61e-7 | 75 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.00011 | 0.00011 | rare |
| South Asian | 0.000034 | 0.000033 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Cleaves P(1)-P(3)-bis(5'-adenosyl) triphosphate (Ap3A) to yield AMP and ADP. Can also hydrolyze P(1)-P(4)-bis(5'- adenosyl) tetraphosphate (Ap4A), but has extremely low activity with ATP. Modulates transcriptional activation by CTNNB1 and thereby contributes to regulate the expression of genes essential for cell proliferation and survival, such as CCND1 and BIRC5. Plays a role in the induction of apoptosis via SRC and AKT1 signaling pathways. Inhibits MDM2-mediated proteasomal degradation of p53/TP53 and thereby plays a role in p53/TP53-mediated apoptosis. Induction of apoptosis depends on the ability of FHIT to bind P(1)-P(3)-bis(5'-adenosyl) triphosphate or related compounds, but does not require its catalytic activity, it may in part come from the mitochondrial form, which sensitizes the low- affinity Ca(2+) transporters, enhancing mitochondrial calcium uptake. Functions as tumor suppressor. {ECO:0000269|PubMed:12574506, ECO:0000269|PubMed:15313915, ECO:0000269|PubMed:16407838, ECO:0000269|PubMed:18077326, ECO:0000269|PubMed:19622739, ECO:0000269|PubMed:8794732, ECO:0000269|PubMed:9323207}.;
- Disease
- DISEASE: Note=A chromosomal aberration involving FHIT has been found in a lymphoblastoid cell line established from a family with renal cell carcinoma and thyroid carcinoma. Translocation t(3;8)(p14.2;q24.1) with RNF139. Although the 3p14.2 breakpoint has been shown to interrupt FHIT in its 5-prime non-coding region, it is unlikely that FHIT is causally related to renal or other malignancies. {ECO:0000269|PubMed:15007172}.; DISEASE: Note=Associated with digestive tract cancers. Numerous tumor types are found to have aberrant forms of FHIT protein due to deletions in a coding region of chromosome 3p14.2 including the fragile site locus FRA3B. {ECO:0000269|PubMed:15007172}.;
Intolerance Scores
- LoFtool
- 0.175
- RVIS EVS
- -0.56
- RVIS percentile EVS
- 19.31
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Indispensability pred.
- E
- Indispensability score
- 0.978
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |