FTO

protein-coding

FTO alpha-ketoglutarate dependent dioxygenase, the group of Alkylation repair homologs

Gene summary

This gene is a nuclear protein of the AlkB related non-haem iron and 2-oxoglutarate-dependent oxygenase superfamily but the exact physiological function of this gene is not known. Other non-heme iron enzymes function to reverse alkylated DNA and RNA damage by oxidative demethylation. Studies in mice and humans indicate a role in nervous and cardiovascular systems and a strong association with body mass index, obesity risk, and type 2 diabetes. [provided by RefSeq, Jul 2011]

MANE transcript

NM_001080432.3

Inheritance

ClinVar variants

P:3U:113B:54

Top phenotype

Growth retardation, developmental delay, and facial dysmorphism

gnomAD constraint

pLI —, LoF o/e 0.56

Max pathogenic AF

—

Genomic locus

chr16:53,701,692-54,158,512

External References & Databases

Ensembl (ENSG00000140718)

Transcript & Mutation Effects

hg38 • Region Span ~456.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

lethal polymalformative syndrome, Boissel typeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013050

Submitter: G2P

lethal polymalformative syndrome, Boissel typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013050

Submitter: Labcorp Genetics (formerly Invitae)

lethal polymalformative syndrome, Boissel typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013050

Submitter: PanelApp Australia

lethal polymalformative syndrome, Boissel typeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013050

Submitter: Orphanet

Clinical Genomic Database (CGD)

Growth retardation, developmental delay, and facial dysmorphismAR

Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Genitourinary; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Comments: The condition can include multiple congenital anomalies

Refs: 19559399; 26378117

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FTO variants in ClinVar

8 Conditions Cataloged

not providedTotal: 131

Inborn genetic diseasesTotal: 54

Lethal polymalformative syndrome, Boissel typeTotal: 41

not specifiedTotal: 14

Meniere diseaseTotal: 3

Body mass index quantitative trait locus 14Total: 1

FTO-related disorderTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001080432.3. 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 clinvar	44 clinvar	1 clinvar	46
missense	1 clinvar	1 clinvar	102 clinvar	7 clinvar	2 clinvar	113
nonsense			5 clinvar			5
start loss			1 clinvar			1
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)		1 clinvar	3 clinvar			4
Total	1	2	113	51	3	170

Highest pathogenic variant AF is 0.0000049601267

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 65 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001080432.3	RefSeq	NP_001073901.1	9	MANE Select
ENST00000471389.6	Ensembl	ENSP00000418823.1	9	MANE Select
NM_001363891.2	RefSeq	NP_001350820.1	9	Standard
NM_001363894.2	RefSeq	NP_001350823.1	10	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
fto	Danio rerio	Structure: melanocyte Quality: mislocalised abnormal

Gene / Model

Organism

Observed Phenotype

fto

Danio rerio

Structure: melanocyte

Quality: mislocalised

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

FTO Obesity Variant Mechanism
DNA Repair
Reversal of alkylation damage by DNA dioxygenases
DNA Damage Reversal

Biological Process

temperature homeostasis
DNA dealkylation involved in DNA repair
regulation of lipid storage
oxidative single-stranded DNA demethylation
oxidative single-stranded RNA demethylation

Molecular Function

ferrous iron binding
oxidative RNA demethylase activity
oxidative DNA demethylase activity
DNA-N1-methyladenine dioxygenase activity
RNA N6-methyladenosine dioxygenase activity

Cellular Component

nucleus
nucleoplasm
cytoplasm
nuclear speck

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000471389
Coding exons: 9
Length: 417979
Individuals with no LoFs: 125718
Homozygous LoFs: 0
Heterozygous LoFs: 30
Defined: 125748
p: 0.000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.562	243	269	0.904	0.0000147	3322
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.000097	0.000097	rare
South Asian	0.00036	0.00036	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

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}.;

Recessive Scores

pRec: 0.280

Intolerance Scores

LoFtool: 0.392
RVIS EVS: -0.29
RVIS percentile EVS: 33.42

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.513

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium