FTO
FTO alpha-ketoglutarate dependent dioxygenase, the group of Alkylation repair homologs
Basic information
Region (hg38): 16:53701692-54158512
Links
Phenotypes
GenCC
Source:
- lethal polymalformative syndrome, Boissel type (Limited), mode of inheritance: AR
- lethal polymalformative syndrome, Boissel type (Supportive), mode of inheritance: AR
- lethal polymalformative syndrome, Boissel type (Strong), mode of inheritance: AR
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Growth retardation, developmental delay, and facial dysmorphism | AR | Cardiovascular | The condition can involve congenital cardiac anomalies, and awareness may allow early management | Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Genitourinary; Musculoskeletal; Neurologic | 19559399; 26378117 |
| The condition can include multiple congenital anomalies |
ClinVar
This is a list of variants' phenotypes submitted to
- not_provided (122 variants)
- Inborn_genetic_diseases (48 variants)
- Lethal_polymalformative_syndrome,_Boissel_type (41 variants)
- Meniere_disease (3 variants)
- not_specified (2 variants)
- Meckel-Gruber_syndrome (1 variants)
- Body_mass_index_quantitative_trait_locus_14 (1 variants)
- Nephronophthisis (1 variants)
- FTO-related_disorder (1 variants)
- Joubert_syndrome (1 variants)
- See_cases (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the FTO gene is commonly pathogenic or not. These statistics are base on transcript: NM_001080432.3. Only rare variants are included in the table.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUSVUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 40 | 43 | ||||
| missense | 92 | 102 | ||||
| nonsense | 6 | |||||
| start loss | 1 | 1 | ||||
| frameshift | 1 | |||||
| splice donor/acceptor (+/-2bp) | 2 | |||||
| Total | 2 | 1 | 102 | 46 | 4 |
Highest pathogenic variant AF is 0.0000049601267
Loading clinvar variants...
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| FTO | protein_coding | protein_coding | ENST00000471389 | 9 | 417979 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 8.36e-8 | 0.979 | 125718 | 0 | 30 | 125748 | 0.000119 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 0.562 | 243 | 269 | 0.904 | 0.0000147 | 3322 |
| Missense in Polyphen | 109 | 119.16 | 0.91474 | 1458 | ||
| Synonymous | -0.538 | 110 | 103 | 1.07 | 0.00000603 | 947 |
| Loss of Function | 2.18 | 16 | 28.6 | 0.560 | 0.00000159 | 306 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000119 | 0.000119 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.000109 | 0.000109 |
| Finnish | 0.0000924 | 0.0000924 |
| European (Non-Finnish) | 0.0000971 | 0.0000967 |
| Middle Eastern | 0.000109 | 0.000109 |
| South Asian | 0.000359 | 0.000359 |
| Other | 0.000163 | 0.000163 |
dbNSFP
Source:
- Function
- FUNCTION: Dioxygenase that repairs alkylated DNA and RNA by oxidative demethylation. Has highest activity towards single- stranded RNA containing 3-methyluracil, followed by single- stranded DNA containing 3-methylthymine. Has low demethylase activity towards single-stranded DNA containing 1-methyladenine or 3-methylcytosine (PubMed:18775698, PubMed:20376003). Specifically demethylates N(6)-methyladenosine (m6A) RNA, the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes (PubMed:22002720, PubMed:26458103). Has no activity towards 1- methylguanine. Has no detectable activity towards double-stranded DNA. Requires molecular oxygen, alpha-ketoglutarate and iron. Contributes to the regulation of the global metabolic rate, energy expenditure and energy homeostasis. Contributes to the regulation of body size and body fat accumulation (PubMed:18775698, PubMed:20376003). In particular, it is involved in the regulation of thermogenesis and the control of adipocyte differentiation into brown or white fat cells (PubMed:26287746). {ECO:0000269|PubMed:18775698, ECO:0000269|PubMed:20376003, ECO:0000269|PubMed:22002720, ECO:0000269|PubMed:26287746, ECO:0000269|PubMed:26458103}.;
- Disease
- DISEASE: Growth retardation, developmental delay, and facial dysmorphism (GDFD) [MIM:612938]: A severe polymalformation syndrome characterized by postnatal growth retardation, microcephaly, severe psychomotor delay, functional brain deficits and characteristic facial dysmorphism. In some patients, structural brain malformations, cardiac defects, genital anomalies, and cleft palate are observed. Early death occurs by the age of 3 years. {ECO:0000269|PubMed:19559399, ECO:0000269|PubMed:22002720, ECO:0000269|PubMed:26378117, ECO:0000269|PubMed:26697951}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Obesity (OBESITY) [MIM:601665]: A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat. {ECO:0000269|PubMed:26287746}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. A pathogenic intronic FTO variation (rs1421085) disrupts an evolutionarily conserved motif for ARID5B binding. Loss of ARID5B binding results in overexpression of two genes distal to FTO, IRX3 and IRX5. IRX3 and IRX5 overexpression shifts pre-adipocytes differentiation from brown to white fat cells, resulting in increased lipid storage and loss of mitochondrial thermogenesis. {ECO:0000269|PubMed:26287746}.;
- Pathway
- FTO Obesity Variant Mechanism;DNA Repair;Reversal of alkylation damage by DNA dioxygenases;DNA Damage Reversal
(Consensus)
Recessive Scores
- pRec
- 0.280
Intolerance Scores
- loftool
- 0.392
- rvis_EVS
- -0.29
- rvis_percentile_EVS
- 33.42
Haploinsufficiency Scores
- pHI
- 0.426
- hipred
- N
- hipred_score
- 0.384
- ghis
- 0.567
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.513
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Fto
- Phenotype
- integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype; skeleton phenotype; renal/urinary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); immune system phenotype;
Zebrafish Information Network
- Gene name
- fto
- Affected structure
- melanocyte
- Phenotype tag
- abnormal
- Phenotype quality
- mislocalised
Gene ontology
- Biological process
- temperature homeostasis;DNA dealkylation involved in DNA repair;regulation of lipid storage;oxidative single-stranded DNA demethylation;oxidative single-stranded RNA demethylation;regulation of multicellular organism growth;RNA repair;regulation of respiratory system process;adipose tissue development;mRNA destabilization;regulation of white fat cell proliferation;oxidative demethylation;DNA demethylation;regulation of brown fat cell differentiation
- Cellular component
- nucleus;nucleoplasm;cytoplasm;nuclear speck
- Molecular function
- ferrous iron binding;oxidative RNA demethylase activity;oxidative DNA demethylase activity;DNA-N1-methyladenine dioxygenase activity;RNA N6-methyladenosine dioxygenase activity;tRNA demethylase activity