FOXO3

protein-coding

forkhead box O3, the group of Forkhead boxes

Gene summary

This gene belongs to the forkhead family of transcription factors which are characterized by a distinct forkhead domain. This gene likely functions as a trigger for apoptosis through expression of genes necessary for cell death. Translocation of this gene with the MLL gene is associated with secondary acute leukemia. Alternatively spliced transcript variants encoding the same protein have been observed. [provided by RefSeq, Jul 2008]

Previous symbols:

FKHRL1
FOXO3A

MANE transcript

NM_001455.4

Inheritance

—

ClinVar variants

U:85B:10

Top phenotype

Medulloblastoma

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr6:108,559,835-108,684,774

External References & Databases

Ensembl (ENSG00000118689)

Transcript & Mutation Effects

hg38 • Region Span ~124.9 kb

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GenCC 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 FOXO3 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 85

not providedTotal: 8

MedulloblastomaTotal: 1

Choroid plexus carcinomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001455.4. 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 clinvar	3 clinvar	5
missense			82 clinvar	4 clinvar	1 clinvar	87
nonsense			2 clinvar			2
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)						0
Total	0	0	85	6	4	95

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001455.4	RefSeq	NP_001446.1	2	MANE Select
ENST00000406360.2	Ensembl	ENSP00000385824.1	2	MANE Select
NM_001415139.1	RefSeq	NP_001402068.1	2	Standard
NM_001415140.1	RefSeq	NP_001402069.1	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
foxo3b	Danio rerio	Structure: head Quality: decreased thickness abnormal

Gene / Model

Organism

Observed Phenotype

foxo3b

Danio rerio

Structure: head

Quality: decreased thickness

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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)

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

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

Cellular Component

nucleus
nucleoplasm
cytoplasm
mitochondrion
mitochondrial outer membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000406360
Coding exons: 2
Length: 124940
Individuals with no LoFs: 125455
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 125456
p: 0.00000399

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.68	288	380	0.757	0.0000228	4349
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.595

Intolerance Scores

RVIS EVS: -0.49
RVIS percentile EVS: 22.36

Essentials

Essential (CRISPR): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.993

Gene Damage Prediction

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