FERMT3
protein-codingFERM domain containing kindlin 3, the group of Fermitins|Pleckstrin homology domain containing|FERM domain containing
Gene summary
Kindlins are a small family of proteins that mediate protein-protein interactions involved in integrin activation and thereby have a role in cell adhesion, migration, differentiation, and proliferation. The protein encoded by this gene has a key role in the regulation of hemostasis and thrombosis. This protein may also help maintain the membrane skeleton of erythrocytes. Mutations in this gene cause the autosomal recessive leukocyte adhesion deficiency syndrome-III (LAD-III). Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~18.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013016
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013016
Submitter: ClinGen
FERMT3 was first reported in relation to autosomal recessive leukocyte adhesion deficiency 3 in 2008 (Mory et al., PMID: 18779414). At least 15 unique variants (primarily nonsense, along with other LoF splicing and frameshift variants, and few inactivating missense variants) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 18 probands in 6 publications (PMIDs: 18779414, 19234463, 19234460, 19064721, 21441448, 22139635). Variants in this gene segregated with disease in two additional family members. More evidence is available in the literature, but the maximum score for genetic and experimental evidence has been reached. This gene-disease relationship is supported by the enhanced expression of FERMT3 in hematopoietic tissues, its biochemical function in integrin activation which is altered in patient cells but can be rescued, and a null mouse model which recapitulates both cellular defects and clinical phenotypes observed in human LAD-III patients. In summary, FERMT3 is definitively associated with autosomal recessive leukocyte adhesion deficiency 3. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0013016
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0013016
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013016
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Hematologic
Intervention: Allergy/Immunology/Infectious; Hematologic
Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; Individuals may have hematologic anomalies, and treatment (which may include RBC and platelet transfusions) may be indicated; BMT has been described
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FERMT3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_031471.6. 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 | 184 | 4 | 189 | ||
| missense | 234 | 16 | 1 | 251 | ||
| nonsense | 6 | 1 | 3 | 10 | ||
| start loss | 1 | 1 | ||||
| frameshift | 10 | 1 | 2 | 13 | ||
| splice donor/acceptor (+/-2bp) | 3 | 6 | 2 | 11 | ||
| Total | 19 | 8 | 243 | 200 | 5 | 475 |
Highest pathogenic variant AF is 0.000006569784
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_113659.3 | 14 | MANE Select | |
| Ensembl | ENSP00000339950.5 | 14 | MANE Select | |
| RefSeq | NP_001369290.1 | 14 | Standard | |
| RefSeq | NP_001369291.1 | 14 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| fermt3b | Danio rerio | Structure: intersegmental vessel Quality: non-functional abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Platelet activation - Homo sapiens (human)
- Platelet degranulation
- Response to elevated platelet cytosolic Ca2+
- Platelet activation, signaling and aggregation
- Hemostasis
Biological Process
- platelet degranulation
- leukocyte cell-cell adhesion
- integrin-mediated signaling pathway
- positive regulation of cell migration
- integrin activation
Molecular Function
- integrin binding
Cellular Component
- podosome
- extracellular region
- membrane
- cell junction
- platelet alpha granule lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000279227
- Coding exons
- 14
- Length
- 17205
- Individuals with no LoFs
- 125696
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 52
- Defined
- 125748
- p
- 0.000207
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.51 | 332 | 419 | 0.793 | 0.0000302 | 4296 |
| Missense (PolyPhen) | 79 | 125.17 | 0.63115 | 1369 | ||
| Synonymous | -0.262 | 188 | 183 | 1.02 | 0.0000130 | 1333 |
| Loss of Function | 3.64 | 13 | 36.8 | 0.353 | 0.00000207 | 370 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00017 | 0.00017 | rare |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.000049 | 0.000046 | rare |
| European (Non-Finnish) | 0.00029 | 0.00029 | rare |
| South Asian | 0.00023 | 0.00023 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays a central role in cell adhesion in hematopoietic cells (PubMed:19234463, PubMed:26359933). Acts by activating the integrin beta-1-3 (ITGB1, ITGB2 and ITGB3) (By similarity). Required for integrin-mediated platelet adhesion and leukocyte adhesion to endothelial cells (PubMed:19234460). Required for activation of integrin beta-2 (ITGB2) in polymorphonuclear granulocytes (PMNs) (By similarity). {ECO:0000250|UniProtKB:Q8K1B8, ECO:0000269|PubMed:19234460, ECO:0000269|PubMed:19234463, ECO:0000269|PubMed:26359933}.;
- Disease
- DISEASE: Leukocyte adhesion deficiency 3 (LAD3) [MIM:612840]: A disorder characterized by recurrent bacterial infections without pus formation, leukocytosis and major bleeding disorders. {ECO:0000269|PubMed:18779414, ECO:0000269|PubMed:19064721, ECO:0000269|PubMed:19234460, ECO:0000269|PubMed:19234463, ECO:0000269|PubMed:19617577, ECO:0000269|PubMed:26359933}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.126
Intolerance Scores
- LoFtool
- 0.305
- RVIS EVS
- -0.19
- RVIS percentile EVS
- 39.24
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.813
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |