FAT2

protein-coding

FAT atypical cadherin 2, the group of Cadherin related|MicroRNA protein coding host genes

Gene summary

This gene is the second identified human homolog of the Drosophila fat gene, which encodes a tumor suppressor essential for controlling cell proliferation during Drosophila development. The gene product is a member of the cadherin superfamily, a group of integral membrane proteins characterized by the presence of cadherin-type repeats. In addition to containing 34 tandem cadherin-type repeats, the gene product has two epidermal growth factor (EGF)-like repeats and one laminin G domain. This protein most likely functions as a cell adhesion molecule, controlling cell proliferation and playing an important role in cerebellum development. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001447.3

Inheritance

ClinVar variants

P:1U:982B:494

Top phenotype

Spinocerebellar ataxia 45

gnomAD constraint

pLI —, LoF o/e 0.4

Max pathogenic AF

—

Genomic locus

chr5:151,504,092-151,591,331

External References & Databases

Ensembl (ENSG00000086570)

Transcript & Mutation Effects

hg38 • Region Span ~87.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spinocerebellar ataxia 45LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0033480

Submitter: Labcorp Genetics (formerly Invitae)

spinocerebellar ataxia 45LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0033480

Submitter: Ambry Genetics

spinocerebellar ataxia 45LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0033480

Submitter: Illumina

The FAT2 gene is located on chromosome 5 at 5q33.1 and encodes the FAT atypical cadherin 2 protein, which helps regulate cell migration and is thought to be involved in cerebellar development by organizing the parallel fibers of granule cells. The FAT2 gene was first reported in relation to autosomal dominant spinocerebellar ataxia in 2017 (29053796: Nibbeling et al. 2017). Evidence supporting this gene-disease relationship includes limited case-level and experimental data. Heterozygous missense variants were identified in two unrelated individuals (29053796: Nibbeling et al. 2017). One of the variants segregated with the disease in six additional family members. The mechanism of disease is unknown, but in vitro analyses of the identified variants suggested they resulted in partial protein mislocalization to the golgi and in one case, increased cellular aggregation in the presence of calcium. FAT2 is also almost exclusively expressed in the cerebellum, where it localizes to the parallel fibers of granule cells (12213440: Nakayama et al. 2002). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.

spinocerebellar ataxia 45STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033480

Submitter: PanelApp Australia

spinocerebellar ataxia 45SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0033480

Submitter: Orphanet

Clinical Genomic Database (CGD)

Spinocerebellar ataxia 45AD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 29053796

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FAT2 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 974

not specifiedTotal: 816

FAT2-related disorderTotal: 79

Spinocerebellar ataxia 45Total: 36

Cerebellar ataxiaTotal: 1

Spastic ataxiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001447.3. 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			9 clinvar	310 clinvar	14 clinvar	333
missense		1 clinvar	945 clinvar	152 clinvar	18 clinvar	1116
nonsense			12 clinvar			12
start loss						0
frameshift			13 clinvar			13
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	1	982	462	32	1477

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001447.3	RefSeq	NP_001438.1	23	MANE Select
ENST00000261800.6	Ensembl	ENSP00000261800.5	23	MANE Select
ENST00000520200.5	Ensembl	ENSP00000429678.1	11	Standard
XM_011537600.3	RefSeq	XP_011535902.1	23	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

homophilic cell adhesion via plasma membrane adhesion molecules
epithelial cell migration
cell-substrate adhesion

Molecular Function

calcium ion binding

Cellular Component

Golgi apparatus
plasma membrane
cell-cell adherens junction
integral component of membrane
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261800
Coding exons: 23
Length: 64852
Individuals with no LoFs: 125593
Homozygous LoFs: 0
Heterozygous LoFs: 155
Defined: 125748
p: 0.000616

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.717	2292	2.39e+3	0.959	0.000133	28451
Missense (PolyPhen)		757	868.15	0.87197		11021
Synonymous	-1.00	1023	983	1.04	0.0000576	9010
Loss of Function	6.38	54	134	0.404	0.00000759	1582

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00093	0.00092	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00071	0.00071	rare
Finnish	0.00042	0.00042	rare
European (Non-Finnish)	0.00085	0.00083	rare
South Asian	0.00026	0.00026	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the regulation of cell migration (PubMed:18534823). May be involved in mediating the organization of the parallel fibers of granule cells during cerebellar development (By similarity). {ECO:0000250|UniProtKB:O88277, ECO:0000269|PubMed:18534823}.;

Recessive Scores

pRec: 0.0970

Intolerance Scores

LoFtool: 0.642
RVIS EVS: 1.95
RVIS percentile EVS: 97.53

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.296

Gene Damage Prediction

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