FTO

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

Basic information

Region (hg38): 16:53701691-54158512

Links

ENSG00000140718 ∙ NCBI:79068 ∙ OMIM:610966 ∙ HGNC:24678 ∙ Uniprot:Q9C0B1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 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: CGD

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 ClinVar and linked to the FTO gene.

• Lethal polymalformative syndrome, Boissel type (114 variants)
• not provided (98 variants)
• Inborn genetic diseases (20 variants)
• Nephronophthisis (1 variants)
• Familial aplasia of the vermis (1 variants)
• Meckel-Gruber 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.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	27	2	31
missense			66	7	3	76
nonsense			3			3
start loss			1			1
frameshift			1			1
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			3	5		8
non coding			43	9	27	79
Total	0	0	116	43	32

Variants in FTO

This is a list of pathogenic ClinVar variants found in the FTO region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
16-53703648-G-A			Benign (Feb 24, 2021)
16-53703803-C-A		Meckel syndrome, type 5 • Nephronophthisis 8 • Joubert syndrome 7	Uncertain significance (Jan 13, 2018)
16-53703804-G-A		Joubert syndrome 7 • Meckel syndrome, type 5 • Nephronophthisis 8	Uncertain significance (Jan 13, 2018)
16-53703811-T-C		Meckel syndrome, type 5 • Joubert syndrome 7 • Nephronophthisis 8	Uncertain significance (Jan 13, 2018)
16-53703813-G-A			Likely benign (Apr 11, 2018)
16-53703823-T-A		not specified	Likely benign (Aug 08, 2016)
16-53703857-G-A		Joubert syndrome 7 • Nephronophthisis 8 • Meckel syndrome, type 5	Uncertain significance (Jan 13, 2018)
16-53703975-A-T		Lethal polymalformative syndrome, Boissel type	Uncertain significance (Apr 27, 2017)
16-53703999-C-G		Lethal polymalformative syndrome, Boissel type	Uncertain significance (Jan 13, 2018)
16-53704017-C-G		Lethal polymalformative syndrome, Boissel type	Uncertain significance (Jan 13, 2018)
16-53704045-T-C		Lethal polymalformative syndrome, Boissel type	Likely benign (Jan 13, 2018)
16-53704048-G-C		Lethal polymalformative syndrome, Boissel type	Uncertain significance (Jan 12, 2018)
16-53704063-C-G		Lethal polymalformative syndrome, Boissel type	Uncertain significance (Jan 12, 2018)
16-53704142-G-A		Lethal polymalformative syndrome, Boissel type	Uncertain significance (Jan 13, 2018)
16-53704179-G-A		Lethal polymalformative syndrome, Boissel type	Uncertain significance (Jan 13, 2018)
16-53704180-GC-G		Lethal polymalformative syndrome, Boissel type	Uncertain significance (Jun 14, 2016)
16-53704185-A-G		Lethal polymalformative syndrome, Boissel type	Uncertain significance (Dec 26, 2022)
16-53704191-C-T		Inborn genetic diseases	Uncertain significance (Nov 09, 2021)
16-53704192-G-C			Uncertain significance (Oct 02, 2023)
16-53704194-A-G			Uncertain significance (Sep 17, 2021)
16-53704196-C-G			Benign (Jan 18, 2024)
16-53704202-T-C		Meckel-Gruber syndrome • Familial aplasia of the vermis • Lethal polymalformative syndrome, Boissel type • Nephronophthisis	Benign/Likely benign (Jan 28, 2024)
16-53704237-G-T		Lethal polymalformative syndrome, Boissel type	Conflicting classifications of pathogenicity (Oct 13, 2022)
16-53704239-G-A			Likely benign (Jun 28, 2022)
16-53767042-T-C		OBESITY (BMIQ14), SUSCEPTIBILITY TO	risk factor (Sep 03, 2015)

GnomAD

Source: gnomAD

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: 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}.
• 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