FLRT3
protein-codingfibronectin leucine rich transmembrane protein 3, the group of Fibronectin type III domain containing
Gene summary
This gene encodes a member of the fibronectin leucine rich transmembrane protein (FLRT) family. FLRTs may function in cell adhesion and/or receptor signalling. Their protein structures resemble small leucine-rich proteoglycans found in the extracellular matrix. This gene is expressed in many tissues. Two alternatively spliced transcript variants encoding the same protein have been described for this gene. [provided by RefSeq, Jul 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~14.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0018800
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014107
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014107
Submitter: PanelApp Australia
Inheritance Pattern: Unknown
Disease ID:MONDO:0014107
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Endocrine; Musculoskeletal; Neurologic
Intervention: Endocrine
Rationale: In Hypogonadotropic hypogonadism, surveillance in adolescence related to sexual maturation is indicated, as is monitoring of bone mineral density in order to allow early detection and treatment of disease; In order to induce and maintain secondary sex characteristics, gradually increasing doses of gonadal steroids (females: estrogen/progestin; males: testosterone/hCG) can be beneficial; Related to fertility, endocrinologic therapy (females: recombinant hCG or pulsatile GnRH therapy; males: hCG/HMG/recombinant FSH or pulsatile GnRH therapy) may be effective, though IVF may be required
Comments: Relatively complex genetic models of disease have been described (eg, involving variants in other FGF8-network-associated genes)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FLRT3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_198391.3. 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 | 23 | 2 | 25 | |||
| missense | 1 | 89 | 4 | 94 | ||
| nonsense | 2 | 2 | ||||
| start loss | 0 | |||||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 1 | 0 | 93 | 27 | 2 | 123 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_938205.1 | 1 | MANE Select | |
| Ensembl | ENSP00000339912.4 | 1 | MANE Select | |
| RefSeq | NP_037413.1 | 1 | Standard | |
| Ensembl | ENSP00000367292.3 | 1 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Developmental Biology
- Signal Transduction
- Signaling by FGFR
- Signaling by ROBO receptors
- Axon guidance
Biological Process
- proepicardium cell migration involved in pericardium morphogenesis
- axon guidance
- synapse assembly
- heart development
- fibroblast growth factor receptor signaling pathway
Molecular Function
- fibroblast growth factor receptor binding
- protein binding
- protein binding, bridging
- protein homodimerization activity
- chemorepellent activity
Cellular Component
- extracellular space
- endoplasmic reticulum membrane
- cytosol
- plasma membrane
- integral component of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000378053
- Coding exons
- 1
- Length
- 14629
- Individuals with no LoFs
- 125659
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 9
- Defined
- 125668
- p
- 0.0000358
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.86 | 254 | 352 | 0.721 | 0.0000185 | 4250 |
| Missense (PolyPhen) | 70 | 134.6 | 0.52004 | 1614 | ||
| Synonymous | -0.116 | 131 | 129 | 1.01 | 0.00000642 | 1324 |
| Loss of Function | 3.14 | 5 | 20.2 | 0.247 | 0.00000133 | 231 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000053 | 0.000053 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Functions in cell-cell adhesion, cell migration and axon guidance, exerting an attractive or repulsive role depending on its interaction partners. Plays a role in the spatial organization of brain neurons. Plays a role in vascular development in the retina (By similarity). Plays a role in cell-cell adhesion via its interaction with ADGRL3 and probably also other latrophilins that are expressed at the surface of adjacent cells (PubMed:26235030). Interaction with the intracellular domain of ROBO1 mediates axon attraction towards cells expressing NTN1. Mediates axon growth cone collapse and plays a repulsive role in neuron guidance via its interaction with UNC5B, and possibly also other UNC-5 family members (By similarity). Promotes neurite outgrowth (in vitro) (PubMed:14706654). Mediates cell-cell contacts that promote an increase both in neurite number and in neurite length. Plays a role in the regulation of the density of glutamaergic synapses. Plays a role in fibroblast growth factor-mediated signaling cascades. Required for normal morphogenesis during embryonic development, but not for normal embryonic patterning. Required for normal ventral closure, headfold fusion and definitive endoderm migration during embryonic development. Required for the formation of a normal basement membrane and the maintenance of a normal anterior visceral endoderm during embryonic development (By similarity). {ECO:0000250|UniProtKB:B1H234, ECO:0000250|UniProtKB:Q8BGT1, ECO:0000269|PubMed:14706654, ECO:0000269|PubMed:26235030}.;
- Disease
- DISEASE: Hypogonadotropic hypogonadism 21 with or without anosmia (HH21) [MIM:615271]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic- pituitary axis. In some cases, it is associated with non- reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). {ECO:0000269|PubMed:23643382}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. Some patients carrying mutations in FLRT3 also have a mutation in another HH-associated gene including FGFR1, HS6ST1 and FGF17 (PubMed:23643382). {ECO:0000269|PubMed:23643382}.;
Recessive Scores
- pRec
- 0.122
Intolerance Scores
- LoFtool
- 0.146
- RVIS EVS
- -0.09
- RVIS percentile EVS
- 46.99
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.484
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |