FAT4

FAT atypical cadherin 4, the group of Cadherin related

Basic information

Region (hg38): 4:125314917-125492932

Links

ENSG00000196159 ∙ NCBI:79633 ∙ OMIM:612411 ∙ HGNC:23109 ∙ Uniprot:Q6V0I7 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Hennekam lymphangiectasia-lymphedema syndrome 2 (Definitive), mode of inheritance: AR
• van Maldergem syndrome 2 (Definitive), mode of inheritance: AR
• Hennekam syndrome (Supportive), mode of inheritance: AR
• van Maldergem syndrome (Supportive), mode of inheritance: AR
• Hennekam lymphangiectasia-lymphedema syndrome 2 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hennekam lymphangiectasia-lymphedema syndrome 2	AR	Allergy/Immunology/Infectious; Gastrointestinal	The condition can include manifestations such as protein-losing enteropathy (which may be refractory), as well as features for which treatment can be beneficial, such as infectious sequelae, for which early and aggressive treatment may be beneficial	Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Craniofacial; Dental; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Pulmonary; Renal	2624276; 22469822; 22473091; 24056717; 24913602

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FAT4 gene.

• not provided (2068 variants)
• Inborn genetic diseases (225 variants)
• not specified (125 variants)
• Hennekam lymphangiectasia-lymphedema syndrome 2 (39 variants)
• Van Maldergem syndrome 2 (37 variants)
• FAT4-related condition (18 variants)
• Hennekam lymphangiectasia-lymphedema syndrome 2;Van Maldergem syndrome 2 (10 variants)
• Van Maldergem syndrome 2;Hennekam lymphangiectasia-lymphedema syndrome 2 (7 variants)
• Capillary infantile hemangioma (2 variants)
• 7 conditions (2 variants)
• Congenital anomaly of kidney and urinary tract (2 variants)
• Hennekam lymphangiectasia-lymphedema syndrome 1 (2 variants)
• Van Maldergem syndrome (1 variants)
• Irido-corneo-trabecular dysgenesis;Anophthalmia-microphthalmia syndrome (1 variants)
• Anophthalmia-microphthalmia syndrome (1 variants)
• Microcephaly (1 variants)
• See cases (1 variants)
• Van Maldergem syndrome 1;Van Maldergem syndrome 2;Hennekam lymphangiectasia-lymphedema syndrome 1;Hennekam lymphangiectasia-lymphedema syndrome 2 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FAT4 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			12	632	33	677
missense		1	1193	63	26	1283
nonsense	8	4	1			13
start loss						0
frameshift	9	1	6			16
inframe indel			6			6
splice donor/acceptor (+/-2bp)	2	1		1		4
splice region			5	16	2	23
non coding			2	69	53	124
Total	19	7	1220	765	112

Variants in FAT4

This is a list of pathogenic ClinVar variants found in the FAT4 region.

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

Position	Type	Phenotype	Significance	ClinVar
4-125316086-A-G			Benign (Jun 14, 2018)
4-125316421-G-A			Uncertain significance (Aug 22, 2022)
4-125316435-T-C			Likely benign (Jun 29, 2023)
4-125316436-A-T		Inborn genetic diseases	Uncertain significance (Jul 05, 2023)
4-125316448-T-C			Uncertain significance (Aug 09, 2021)
4-125316453-C-G			Likely benign (Apr 17, 2023)
4-125316453-C-T			Likely benign (May 03, 2022)
4-125316455-C-G			Uncertain significance (Apr 12, 2021)
4-125316466-C-T			Likely benign (Nov 10, 2022)
4-125316471-A-G			Likely benign (Aug 24, 2023)
4-125316472-G-C			Uncertain significance (Jun 09, 2022)
4-125316489-A-G			Likely benign (Jun 24, 2022)
4-125316492-G-A			Likely benign (Aug 01, 2022)
4-125316500-T-C			Uncertain significance (Dec 19, 2023)
4-125316501-A-G			Likely benign (Nov 08, 2022)
4-125316502-C-T		FAT4-related disorder	Likely benign (Oct 20, 2021)
4-125316515-C-T			Uncertain significance (Mar 23, 2022)
4-125316516-G-C			Likely benign (Dec 17, 2020)
4-125316526-T-C			Uncertain significance (Feb 11, 2020)
4-125316531-C-T			Likely benign (Aug 01, 2023)
4-125316535-G-C			Uncertain significance (May 04, 2022)
4-125316540-C-G			Likely benign (Nov 28, 2023)
4-125316542-A-C		Anophthalmia-microphthalmia syndrome;Irido-corneo-trabecular dysgenesis	Conflicting classifications of pathogenicity (Jan 20, 2024)
4-125316543-G-A			Likely benign (May 11, 2022)
4-125316543-G-C		Inborn genetic diseases	Uncertain significance (Aug 10, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FAT4	protein_coding	protein_coding	ENST00000394329	17	176534

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	1.69e-10	125696	0	52	125748	0.000207

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.622	2545	2.63e+3	0.966	0.000138	32695
Missense in Polyphen		990	1186.1	0.8347		15034
Synonymous	-1.30	1071	1.02e+3	1.05	0.0000556	10185
Loss of Function	9.37	16	132	0.121	0.00000718	1792

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000434	0.000428
Ashkenazi Jewish	0.000397	0.000397
East Asian	0.0000565	0.0000544
Finnish	0.0000945	0.0000924
European (Non-Finnish)	0.000221	0.000220
Middle Eastern	0.0000565	0.0000544
South Asian	0.000425	0.000392
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Cadherins are calcium-dependent cell adhesion proteins. FAT4 plays a role in the maintenance of planar cell polarity as well as in inhibition of YAP1-mediated neuroprogenitor cell proliferation and differentiation (By similarity). {ECO:0000250}.
• Disease: DISEASE: Van Maldergem syndrome 2 (VMLDS2) [MIM:615546]: An autosomal recessive disorder characterized by intellectual disability, typical craniofacial features, auditory malformations resulting in hearing loss, and skeletal and limb malformations. Some patients have renal hypoplasia. Brain MRI typically shows periventricular nodular heterotopia. {ECO:0000269|PubMed:24056717}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hennekam lymphangiectasia-lymphedema syndrome 2 (HKLLS2) [MIM:616006]: A form of Hennekam lymphangiectasia-lymphedema syndrome, a generalized lymph-vessels dysplasia characterized by intestinal lymphangiectasia with severe lymphedema of the limbs, genitalia and face. In addition, affected individuals have unusual facies and severe mental retardation. HKLLS2 individuals have lymphangiectasia variably affecting the gut, pericardium, lungs, kidneys, and genitalia. Other features include camptodactyly and rare syndactyly. {ECO:0000269|PubMed:24913602}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Hippo signaling pathway - multiple species - Homo sapiens (human) (Consensus)

Recessive Scores

• pRec: 0.101

Intolerance Scores

• loftool: 0.323
• rvis_EVS: -0.5
• rvis_percentile_EVS: 21.82

Haploinsufficiency Scores

• pHI: 0.209
• hipred: Y
• hipred_score: 0.544
• ghis: 0.551

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.731

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Fat4
• Phenotype: embryo phenotype; respiratory system 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); hearing/vestibular/ear phenotype; limbs/digits/tail phenotype; digestive/alimentary phenotype; skeleton phenotype; renal/urinary system phenotype; growth/size/body region phenotype; cellular phenotype

Gene ontology

• Biological process: branching involved in ureteric bud morphogenesis;heart morphogenesis;plasma membrane organization;homophilic cell adhesion via plasma membrane adhesion molecules;heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules;Notch signaling pathway;fibroblast growth factor receptor signaling pathway;cerebral cortex development;neurogenesis;hippo signaling;ossification involved in bone maturation;digestive tract development;inner ear receptor cell stereocilium organization;condensed mesenchymal cell proliferation;regulation of metanephric nephron tubule epithelial cell differentiation
• Cellular component: plasma membrane;integral component of membrane;apical part of cell;extracellular exosome
• Molecular function: calcium ion binding;protein binding