FLRT3

fibronectin leucine rich transmembrane protein 3, the group of Fibronectin type III domain containing

Basic information

Region (hg38): 20:14322984-14337614

Links

ENSG00000125848 ∙ NCBI:23767 ∙ OMIM:604808 ∙ HGNC:3762 ∙ Uniprot:Q9NZU0 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hypogonadotropic hypogonadism 21 with or without anosmia (Limited), mode of inheritance: AD
• Kallmann syndrome (Supportive), mode of inheritance: AD
• hypogonadotropic hypogonadism 21 with or without anosmia (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hypogonadotropic hypogonadism 21, with or without anosmia	AD/Digenic/Multigenic	Endocrine	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	Audiologic/Otolaryngologic; Endocrine; Musculoskeletal; Neurologic	6881209; 23643382
Relatively complex genetic models of disease have been described (eg, involving variants in other FGF8-network-associated genes)

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FLRT3 gene.

• not provided (27 variants)
• Inborn genetic diseases (12 variants)
• Hypogonadotropic hypogonadism 21 with or without anosmia (4 variants)
• not specified (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FLRT3 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				9	5	14
missense			23	3	2	28
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding						0
Total	0	0	23	12	7

Variants in FLRT3

This is a list of pathogenic ClinVar variants found in the FLRT3 region.

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

Position	Type	Phenotype	Significance	ClinVar
20-14325600-T-C			Uncertain significance (Nov 16, 2023)
20-14325601-A-G		not specified	Uncertain significance (Jan 22, 2024)
20-14325642-A-G		not specified	Uncertain significance (Feb 05, 2024)
20-14325678-A-G			Uncertain significance (May 01, 2020)
20-14325715-G-A		not specified	Uncertain significance (Oct 26, 2022)
20-14325780-G-A		Hypogonadotropic hypogonadism 21 with or without anosmia	Uncertain significance (Dec 24, 2020)
20-14325865-C-G		High myopia	Uncertain significance (Dec 17, 2018)
20-14325903-C-A		not specified	Uncertain significance (Feb 28, 2023)
20-14325997-G-A		not specified	Uncertain significance (May 18, 2023)
20-14326062-A-T		not specified	Uncertain significance (Nov 09, 2021)
20-14326111-C-G		FLRT3-related disorder • not specified	Uncertain significance (Feb 07, 2024)
20-14326125-C-T			Uncertain significance (Jan 02, 2024)
20-14326127-T-G			Benign (Jan 29, 2024)
20-14326153-T-C			Uncertain significance (May 20, 2020)
20-14326168-G-C		not specified	Uncertain significance (Jan 08, 2024)
20-14326180-G-A		FLRT3-related disorder	Likely benign (Oct 14, 2020)
20-14326184-A-G			Benign (Jan 22, 2024)
20-14326250-G-A		Hypogonadotropic hypogonadism 21 with or without anosmia	Benign (Jan 31, 2024)
20-14326252-T-A		Hypogonadotropic hypogonadism 21 with or without anosmia	Uncertain significance (Aug 22, 2022)
20-14326305-T-A		Amenorrhea	Uncertain significance (Mar 08, 2021)
20-14326307-G-T			Benign (Jan 31, 2024)
20-14326373-T-G			Benign/Likely benign (Feb 01, 2024)
20-14326378-C-T			Benign/Likely benign (Jan 22, 2024)
20-14326395-G-A			Uncertain significance (Jul 14, 2022)
20-14326403-A-G			Benign (Dec 18, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FLRT3	protein_coding	protein_coding	ENST00000378053	1	14629

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.220	0.780	125659	0	9	125668	0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.86	254	352	0.721	0.0000185	4250
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000620	0.0000615
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000463	0.0000462
European (Non-Finnish)	0.0000530	0.0000528
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.000164	0.000163

dbNSFP

Source: dbNSFP

• 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}.
• Pathway: Developmental Biology;Signal Transduction;Signaling by FGFR;Signaling by ROBO receptors;Axon guidance;Signaling by Receptor Tyrosine Kinases;Downstream signaling of activated FGFR1;Signaling by FGFR1 (Consensus)

Recessive Scores

• pRec: 0.122

Intolerance Scores

• loftool: 0.146
• rvis_EVS: -0.09
• rvis_percentile_EVS: 46.99

Haploinsufficiency Scores

• pHI: 0.436
• hipred: Y
• hipred_score: 0.768
• ghis: 0.439

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.484

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Flrt3
• Phenotype: embryo 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); 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); 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); cellular phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: proepicardium cell migration involved in pericardium morphogenesis;axon guidance;synapse assembly;heart development;fibroblast growth factor receptor signaling pathway;neuron projection development;embryonic morphogenesis;response to axon injury;negative chemotaxis;positive regulation of synapse assembly;head development;cell-cell adhesion via plasma-membrane adhesion molecules;synaptic membrane adhesion;neuron projection extension
• Cellular component: extracellular space;endoplasmic reticulum membrane;cytosol;plasma membrane;integral component of plasma membrane;cell-cell junction;focal adhesion;cell junction;extracellular matrix;axon terminus;axonal growth cone;synaptic membrane;glutamatergic synapse;integral component of postsynaptic membrane
• Molecular function: fibroblast growth factor receptor binding;protein binding;protein binding, bridging;protein homodimerization activity;chemorepellent activity