FOXO4

protein-coding

forkhead box O4, the group of Forkhead boxes

Gene summary

This gene encodes a member of the O class of winged helix/forkhead transcription factor family. Proteins encoded by this class are regulated by factors involved in growth and differentiation indicating they play a role in these processes. A translocation involving this gene on chromosome X and the homolog of the Drosophila trithorax gene, encoding a DNA binding protein, located on chromosome 11 is associated with leukemia. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2010]

Previous symbols:

MLLT7

MANE transcript

NM_005938.4

Inheritance

—

ClinVar variants

U:81B:7

Top phenotype

Short 5th metacarpal

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chrX:71,095,851-71,103,535

External References & Databases

Ensembl (ENSG00000184481)

Transcript & Mutation Effects

hg38 • Region Span ~7.7 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 FOXO4 variants in ClinVar

8 Conditions Cataloged

not specifiedTotal: 50

not providedTotal: 4

Short 5th metacarpalTotal: 1

Moderate intellectual disabilityTotal: 1

ClinodactylyTotal: 1

Abnormality of the faceTotal: 1

Intellectual disabilityTotal: 1

MacrocephalyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005938.4. 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			9 clinvar	2 clinvar	1 clinvar	12
missense			63 clinvar	4 clinvar		67
nonsense			6 clinvar			6
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	0	81	6	1	88

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005938.4	RefSeq	NP_005929.2	3	MANE Select
ENST00000374259.8	Ensembl	ENSP00000363377.3	3	MANE Select
NM_001170931.2	RefSeq	NP_001164402.1	4	Standard
ENST00000341558.3	Ensembl	ENSP00000342209.3	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

FoxO signaling pathway - Homo sapiens (human)
Ras signaling pathway - Homo sapiens (human)
IGF-Core
Signaling Pathways in Glioblastoma
AGE-RAGE pathway

Biological Process

negative regulation of transcription by RNA polymerase II
regulation of transcription, DNA-templated
transcription by RNA polymerase II
cell cycle arrest
mitotic G2 DNA damage checkpoint

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
DNA binding
DNA-binding transcription factor activity
protein binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
cytosol
nuclear speck

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000374259
Coding exons: 3
Length: 7339
Individuals with no LoFs: 123635
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 123637
p: 0.00000809

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.65	140	207	0.677	0.0000159	3246
Missense (PolyPhen)		26	65.349	0.39786		1023
Synonymous	1.35	72	88.1	0.817	0.00000689	1122
Loss of Function	2.62	1	9.91	0.101	7.70e-7	156

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)	0.000025	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor involved in the regulation of the insulin signaling pathway. Binds to insulin-response elements (IREs) and can activate transcription of IGFBP1. Down-regulates expression of HIF1A and suppresses hypoxia-induced transcriptional activation of HIF1A-modulated genes. Also involved in negative regulation of the cell cycle. Involved in increased proteasome activity in embryonic stem cells (ESCs) by activating expression of PSMD11 in ESCs, leading to enhanced assembly of the 26S proteasome, followed by higher proteasome activity. {ECO:0000269|PubMed:10217147, ECO:0000269|PubMed:10783894, ECO:0000269|PubMed:12761217, ECO:0000269|PubMed:15126506, ECO:0000269|PubMed:16054032, ECO:0000269|PubMed:16964248, ECO:0000269|PubMed:20874444, ECO:0000269|PubMed:22972301}.;
Disease: DISEASE: Note=A chromosomal aberration involving FOXO4 is found in acute leukemias. Translocation t(X;11)(q13;q23) with KMT2A/MLL1. The result is a rogue activator protein.;

Recessive Scores

pRec: 0.231

Intolerance Scores

LoFtool: 0.118
RVIS EVS: -0.23
RVIS percentile EVS: 36.86

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.959

Gene Damage Prediction

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