FOXO3

forkhead box O3, the group of Forkhead boxes

Basic information

Region (hg38): 6:108559834-108684774

Previous symbols: [ "FKHRL1", "FOXO3A" ]

Links

ENSG00000118689 ∙ NCBI:2309 ∙ OMIM:602681 ∙ HGNC:3821 ∙ Uniprot:O43524 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FOXO3 gene.

• Inborn genetic diseases (22 variants)
• not provided (12 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FOXO3 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	3	5
missense			24		2	26
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding					3	3
Total	0	0	24	2	8

Variants in FOXO3

This is a list of pathogenic ClinVar variants found in the FOXO3 region.

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

Position	Type	Phenotype	Significance	ClinVar
6-108561222-C-T		not specified	Uncertain significance (Aug 08, 2023)
6-108561224-G-T		not specified	Uncertain significance (Jul 17, 2023)
6-108561240-T-G			Uncertain significance (Mar 01, 2022)
6-108561287-C-T		not specified	Uncertain significance (Sep 07, 2022)
6-108561360-C-T		not specified	Uncertain significance (Jan 27, 2022)
6-108561428-G-A		not specified	Uncertain significance (Mar 11, 2022)
6-108561471-T-G		not specified	Uncertain significance (Jun 30, 2023)
6-108561477-C-G		not specified	Uncertain significance (Jan 09, 2024)
6-108561543-C-T		not specified	Uncertain significance (Aug 12, 2021)
6-108561564-T-A		not specified	Uncertain significance (Mar 06, 2023)
6-108561621-C-T		not specified	Uncertain significance (Jul 13, 2021)
6-108561627-C-T			Benign (Dec 31, 2019)
6-108561636-G-T		not specified	Uncertain significance (Jul 21, 2021)
6-108561639-C-G		not specified	Uncertain significance (May 18, 2022)
6-108561640-C-T			Likely benign (Nov 02, 2017)
6-108561641-G-A		not specified	Uncertain significance (Dec 16, 2023)
6-108561712-C-T			Benign (Dec 31, 2019)
6-108561791-A-T		Choroid plexus carcinoma	other (May 01, 2016)
6-108587315-G-T			Benign (Feb 18, 2020)
6-108663532-G-A		Medulloblastoma	other (May 01, 2016)
6-108663580-G-A			Benign (May 30, 2018)
6-108663615-C-T		not specified	Uncertain significance (Sep 16, 2021)
6-108663747-C-T		not specified	Uncertain significance (Oct 29, 2021)
6-108663824-A-G		not specified	Uncertain significance (Dec 20, 2023)
6-108663854-G-A			Benign (Jul 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FOXO3	protein_coding	protein_coding	ENST00000406360	2	124940

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.988	0.0119	125455	0	1	125456	0.00000399

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.68	288	380	0.757	0.0000228	4349
Missense in Polyphen		29	94.856	0.30573		1010
Synonymous	-1.29	187	166	1.13	0.0000105	1407
Loss of Function	3.69	1	17.8	0.0563	8.29e-7	201

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000882	0.00000882
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcriptional activator which triggers apoptosis in the absence of survival factors, including neuronal cell death upon oxidative stress (PubMed:10102273, PubMed:16751106). Recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A-3' (PubMed:21329882). Participates in post-transcriptional regulation of MYC: following phosphorylation by MAPKAPK5, promotes induction of miR-34b and miR-34c expression, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation (PubMed:21329882). In response to metabolic stress, translocates into the mitochondria where it promotes mtDNA transcription (PubMed:23283301). {ECO:0000269|PubMed:10102273, ECO:0000269|PubMed:16751106, ECO:0000269|PubMed:21329882, ECO:0000269|PubMed:23283301}.
• Disease: DISEASE: Note=A chromosomal aberration involving FOXO3 is found in secondary acute leukemias. Translocation t(6;11)(q21;q23) with KMT2A/MLL1.
• Pathway: PI3K-Akt signaling pathway - Homo sapiens (human);Non-small cell lung cancer - Homo sapiens (human);Neurotrophin signaling pathway - Homo sapiens (human);Longevity regulating pathway - multiple species - Homo sapiens (human);FoxO signaling pathway - Homo sapiens (human);Chemokine signaling pathway - Homo sapiens (human);Mitophagy - animal - Homo sapiens (human);AMPK signaling pathway - Homo sapiens (human);Longevity regulating pathway - Homo sapiens (human);Prolactin signaling pathway - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Endometrial cancer - Homo sapiens (human);IGF-Core;IL-5 Signaling Pathway;Energy Metabolism;Signaling Pathways in Glioblastoma;Brain-Derived Neurotrophic Factor (BDNF) signaling pathway;Spinal Cord Injury;Kit receptor signaling pathway;Copper homeostasis;NAD metabolism, sirtuins and aging;Imatinib and Chronic Myeloid Leukemia;Pathways Affected in Adenoid Cystic Carcinoma;PI3K-AKT-mTOR signaling pathway and therapeutic opportunities;VEGFA-VEGFR2 Signaling Pathway;Angiopoietin Like Protein 8 Regulatory Pathway;Chemokine signaling pathway;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;HDAC6 interactions;Interleukin-4 and 13 signaling;Endometrial cancer;PI3K-Akt Signaling Pathway;Insulin Signaling;IL-2 Signaling Pathway;DNA Damage Response (only ATM dependent);Developmental Biology;RAGE;Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer,s disease models;Neurodegenerative Diseases;Disease;Signal Transduction;Gene expression (Transcription);RUNX3 regulates BCL2L11 (BIM) transcription;Transcriptional regulation by RUNX3;akt signaling pathway;pten dependent cell cycle arrest and apoptosis;Generic Transcription Pathway;MAPK6/MAPK4 signaling;RNA Polymerase II Transcription;p73 transcription factor network;AKT phosphorylates targets in the nucleus;insulin Mam;BCR;Signaling by NODAL;TGF_beta_Receptor;role of nicotinic acetylcholine receptors in the regulation of apoptosis;BDNF;the igf-1 receptor and longevity;MAPK family signaling cascades;PIP3 activates AKT signaling;IL2;Class I PI3K signaling events;IL5;Constitutive Signaling by AKT1 E17K in Cancer;PI3K/AKT Signaling in Cancer;IL6;IL-7;Intracellular signaling by second messengers;Insulin Pathway;Diseases of signal transduction;Validated targets of C-MYC transcriptional repression;IL2 signaling events mediated by PI3K;Signaling events mediated by Stem cell factor receptor (c-Kit);Signaling events mediated by HDAC Class III;FoxO family signaling;Class I PI3K signaling events mediated by Akt;Trk receptor signaling mediated by PI3K and PLC-gamma;Regulation of nuclear SMAD2/3 signaling;insulin (Consensus)

Recessive Scores

• pRec: 0.595

Intolerance Scores

• rvis_EVS: -0.49
• rvis_percentile_EVS: 22.36

Haploinsufficiency Scores

• ghis: 0.459

Essentials

• essential_gene_CRISPR: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.993

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Foxo3
• Phenotype: reproductive 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); hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); neoplasm; pigmentation phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; renal/urinary system phenotype; skeleton phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; vision/eye 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); endocrine/exocrine gland phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); cellular phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: foxo3b
• Affected structure: head
• Phenotype tag: abnormal
• Phenotype quality: decreased thickness

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;ovulation from ovarian follicle;initiation of primordial ovarian follicle growth;antral ovarian follicle growth;oocyte maturation;regulation of transcription by RNA polymerase II;mitochondrial transcription;regulation of translation;aging;insulin receptor signaling pathway;cytokine-mediated signaling pathway;DNA damage response, signal transduction by p53 class mediator;negative regulation of cell migration;response to nutrient levels;tumor necrosis factor-mediated signaling pathway;cellular response to oxidative stress;glucose homeostasis;positive regulation of apoptotic process;positive regulation of neuron apoptotic process;positive regulation of erythrocyte differentiation;negative regulation of neuron differentiation;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;brain morphogenesis;cellular response to glucose stimulus;cellular response to corticosterone stimulus;cellular response to hypoxia;response to dexamethasone;negative regulation of canonical Wnt signaling pathway;neuronal stem cell population maintenance;extrinsic apoptotic signaling pathway in absence of ligand;positive regulation of hydrogen peroxide-mediated programmed cell death;positive regulation of reactive oxygen species biosynthetic process;cellular response to amyloid-beta;cellular response to nerve growth factor stimulus;response to water-immersion restraint stress;regulation of neural precursor cell proliferation;positive regulation of endothelial cell apoptotic process
• Cellular component: nucleus;nucleoplasm;cytoplasm;mitochondrion;mitochondrial outer membrane;mitochondrial matrix;cytosol;protein-containing complex
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;transcription cofactor binding;DNA-binding transcription repressor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;DNA binding;DNA-binding transcription factor activity;protein binding;beta-catenin binding;transcription factor binding;protein kinase binding;chromatin DNA binding;mitochondrial sequence-specific DNA-binding transcription factor activity;sequence-specific DNA binding