GeneBe

FOXL2

protein-coding

forkhead box L2, the group of Forkhead boxes

Gene summary

This gene encodes a forkhead transcription factor. The protein contains a fork-head DNA-binding domain and may play a role in ovarian development and function. Expansion of a polyalanine repeat region and other mutations in this gene are a cause of blepharophimosis syndrome and premature ovarian failure 3. [provided by RefSeq, Jul 2016]

Previous symbols:
  • BPES

MANE transcript

NM_023067.4

Inheritance

AD

ClinVar variants

P:177U:97B:36

Top phenotype

Blepharophimosis, epicanthus inversus, and ptosis; Premature ovarian failure 3

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr3:138,944,224-138,947,137

External References & Databases

Ensembl (ENSG00000183770)NCBI Gene (668)OMIM (605597)HGNC:1092GenCCUniProt (P58012)AlphaFoldClinVar (FOXL2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~2.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

premature ovarian failure 3LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0012169

Submitter: Labcorp Genetics (formerly Invitae)

blepharophimosis, ptosis, and epicanthus inversus syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007201

Submitter: Labcorp Genetics (formerly Invitae)

blepharophimosis, ptosis, and epicanthus inversus syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007201

Submitter: G2P

blepharophimosis, ptosis, and epicanthus inversus syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007201

Submitter: PanelApp Australia

blepharophimosis, ptosis, and epicanthus inversus syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007201

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Blepharophimosis, epicanthus inversus, and ptosis; Premature ovarian failure 3AD

Manifestation: Craniofacial; Endocrine; Genitourinary; Obstetric; Ophthalmologic

Intervention: Obstetric

Rationale: Awareness may be beneficial to allow interventions such as preserving eggs in women with premature ovarian insufficiency (which is also reported in women with BPES)

Refs: 11175783; 12149404; 15962237; 16283882; 17089161; 19429596; 21325395Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FOXL2 variants in ClinVar

14 Conditions Cataloged
Blepharophimosis, ptosis, and epicanthus inversus syndromeTotal: 135
not providedTotal: 121
Inborn genetic diseasesTotal: 58
FOXL2-related disorderTotal: 26
FOXL2-related disordersTotal: 22
Premature ovarian failure 3Total: 21
not specifiedTotal: 18
BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE ITotal: 11

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_023067.4. 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.

EffectPLPVUSLBBSum
synonymous
3
clinvar
26
clinvar
6
clinvar
 35
missense
9
clinvar
32
clinvar
92
clinvar
3
clinvar
1
clinvar
 137
nonsense
29
clinvar
5
clinvar
 34
start loss
1
clinvar
 1
frameshift
82
clinvar
20
clinvar
1
clinvar
 103
splice donor/acceptor (+/-2bp)
0
Total1205797297310

Highest pathogenic variant AF is 0.0001700949

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_023067.4RefSeqNP_075555.11MANE Select
ENST00000648323.1EnsemblENSP00000497217.11MANE Select

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
foxl2bDanio rerio

Structure: oocyte

Quality: increased occurrence

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • SUMOylation of transcription factors
  • Post-translational protein modification
  • SUMO E3 ligases SUMOylate target proteins
  • Metabolism of proteins
  • SUMOylation

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • ovarian follicle development
  • oocyte growth
  • extraocular skeletal muscle development
  • apoptotic DNA fragmentation

Molecular Function

  • RNA polymerase II proximal promoter sequence-specific DNA binding
  • 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

Cellular Component

  • nucleus
  • nucleoplasm
  • intercellular bridge

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000330315
Coding exons
1
Length
2917
Individuals with no LoFs
0
Homozygous LoFs
0
Heterozygous LoFs
0
Defined
0
p
0.00
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.761091750.6240.000008012370
Missense (PolyPhen)1340.5370.32069468
Synonymous-0.5218478.11.070.00000390822
Loss of Function2.4206.850.002.93e-790

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Transcriptional regulator. Critical factor essential for ovary differentiation and maintenance, and repression of the genetic program for somatic testis determination. Prevents trans- differentiation of ovary to testis through transcriptional repression of the Sertoli cell-promoting gene SOX9 (By similarity). Has apoptotic activity in ovarian cells. Suppresses ESR1-mediated transcription of PTGS2/COX2 stimulated by tamoxifen (By similarity). Is a regulator of CYP19 expression (By similarity). Participates in SMAD3-dependent transcription of FST via the intronic SMAD-binding element (By similarity). Is a transcriptional repressor of STAR. Activates SIRT1 transcription under cellular stress conditions. Activates transcription of OSR2. {ECO:0000250, ECO:0000269|PubMed:16153597, ECO:0000269|PubMed:19010791, ECO:0000269|PubMed:19429596, ECO:0000269|PubMed:19744555}.;
Disease
DISEASE: Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) [MIM:110100]: A disorder characterized by eyelid dysplasia, small palpebral fissures, drooping eyelids and a skin fold curving in the mediolateral direction, inferior to the inner canthus. In type I BPSE (BPES1) eyelid abnormalities are associated with female infertility. Affected females show an ovarian deficit due to primary amenorrhea or to premature ovarian failure (POF). In type II BPSE (BPES2) affected individuals show only the eyelid defects. {ECO:0000269|PubMed:11175783, ECO:0000269|PubMed:11468277, ECO:0000269|PubMed:12400065, ECO:0000269|PubMed:12529855, ECO:0000269|PubMed:12630957, ECO:0000269|PubMed:12938087, ECO:0000269|PubMed:15257268, ECO:0000269|PubMed:16454982, ECO:0000269|PubMed:17089161, ECO:0000269|PubMed:18372316, ECO:0000269|PubMed:18484667, ECO:0000269|PubMed:18642388, ECO:0000269|Ref.2}. Note=The disease is caused by mutations affecting the gene represented in this entry. There is a mutational hotspot in the region coding for the poly-Ala domain, since 30% of all mutations in the ORF lead to poly-Ala expansions, resulting mainly in BPES type II.; DISEASE: Premature ovarian failure 3 (POF3) [MIM:608996]: An ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol. {ECO:0000269|PubMed:12149404, ECO:0000269|PubMed:19429596}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.416

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.953

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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