FYB1
protein-codingFYN binding protein 1
Gene summary
The protein encoded by this gene is an adapter for the FYN protein and LCP2 signaling cascades in T-cells. The encoded protein is involved in platelet activation and controls the expression of interleukin-2. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2011]
- FYB
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~169.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0010120
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0010120
Submitter: ClinGen
*FYB1* was first reported in relation to autosomal recessive thrombocytopenia 3 in 2014 (Hamamy H, et al., PMID: 25516138). At least 2 unique variants (one nonsense and one frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 2 probands in 2 publications (PMIDs: 25516138, 25876182). Variants in this gene segregated with disease in 6 additional family members. This gene-disease relationship is supported by its restricted expression in hematopoietic cells, its biochemical function as an adaptor protein involved in integrin activation, the functional alteration observed in patient and non-patient cells, and both conventional and conditional knockout mouse models. In summary, there is moderate evidence to support the relationship between *FYB1* and autosomal recessive thrombocytopenia 3. Additional reports in humans are needed to reach a definitive classification. This gene-disease pair was previously evaluated by the HT GCEP on December 15, 2021. It was reevaluated on February 5th, 2024. As a result of this reevaluation no new evidence was identified and the classification remained Moderate (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0010120
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Hematologic
Intervention: Hematologic
Rationale: Individuals have been described with bleeding tendency, and awareness may allow early diagnosis, preventive measures, and early and aggressive treatment of bleeding episodes
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FYB1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001465.6. 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 | 1 | 28 | 29 | |||
| missense | 146 | 18 | 2 | 166 | ||
| nonsense | 1 | 1 | 2 | |||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 2 | 0 | 149 | 46 | 2 | 199 |
Highest pathogenic variant AF is 7.3102944e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001456.3 | 18 | MANE Select | |
| Ensembl | ENSP00000425845.3 | 18 | MANE Select | |
| RefSeq | NP_001230022.1 | 19 | Standard | |
| RefSeq | NP_001336262.1 | 18 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Rap1 signaling pathway - Homo sapiens (human)
- T-Cell antigen Receptor (TCR) Signaling Pathway
- Generation of second messenger molecules
- TCR signaling
- TCR
Biological Process
- protein phosphorylation
- NLS-bearing protein import into nucleus
- immune response
- signal transduction
- integrin-mediated signaling pathway
Molecular Function
- signaling receptor binding
- protein binding
- lipid binding
- protein-containing complex binding
Cellular Component
- nucleus
- cytosol
- plasma membrane
- actin cytoskeleton
- cell junction
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000540520
- Coding exons
- 19
- Length
- 169293
- Individuals with no LoFs
- 124678
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 18
- Defined
- 124696
- p
- 0.0000722
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.436 | 437 | 412 | 1.06 | 0.0000204 | 5465 |
| Missense (PolyPhen) | 98 | 102.95 | 0.95189 | 1407 | ||
| Synonymous | -0.991 | 172 | 156 | 1.10 | 0.00000873 | 1585 |
| Loss of Function | 4.37 | 9 | 38.1 | 0.236 | 0.00000181 | 564 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00019 | 0.00019 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00012 | 0.00011 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Acts as an adapter protein of the FYN and LCP2 signaling cascades in T-cells. Modulates the expression of interleukin-2 (IL-2). Involved in platelet activation. Prevents the degradation of SKAP1 and SKAP2. May play a role in linking T-cell signaling to remodeling of the actin cytoskeleton. {ECO:0000269|PubMed:10747096, ECO:0000269|PubMed:15849195, ECO:0000269|PubMed:16980616}.;
- Disease
- DISEASE: Thrombocytopenia 3 (THC3) [MIM:273900]: Thrombocytopenia is defined by a decrease in the number of platelets in circulating blood, resulting in the potential for increased bleeding and decreased ability for clotting. THC3 is an autosomal recessive form characterized by onset in infancy. {ECO:0000269|PubMed:25516138, ECO:0000269|PubMed:25876182}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.197
Intolerance Scores
- RVIS EVS
- -0.18
- RVIS percentile EVS
- 40.56
Essentials
- Essential (gene trap)
- N