FN1
protein-codingfibronectin 1, the group of Fibronectin type III domain containing|Receptor ligands
Gene summary
This gene encodes fibronectin, a glycoprotein present in a soluble dimeric form in plasma, and in a dimeric or multimeric form at the cell surface and in extracellular matrix. The encoded preproprotein is proteolytically processed to generate the mature protein. Fibronectin is involved in cell adhesion and migration processes including embryogenesis, wound healing, blood coagulation, host defense, and metastasis. The gene has three regions subject to alternative splicing, with the potential to produce 20 different transcript variants, at least one of which encodes an isoform that undergoes proteolytic processing. The full-length nature of some variants has not been determined. [provided by RefSeq, Jan 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~75.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008479
Submitter: ClinGen
FN1 was first reported in relation to autosomal dominant spondylometaphyseal dysplasia, corner fracture type (SMDCF) in 2017 (Lee et al., PMID: 29100092). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found clear differences in phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities: autosomal dominant SMDCF (OMIM: 184255) and autosomal dominant glomerulopathy with fibronectin deposits 2 (GFND2; OMIM: 601894). The split curation for GFND2 has been curated separately. 12 variants (missense, in-frame deletion) that have been reported in at least 18 probands in 4 publications (PMIDs: 29100092, 30599297, 33605604, 37940834) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be haploinsufficiency. This gene-disease relationship is also supported by experimental evidence (expression-level evidence; PMIDs: 32561820). Altered expression of FN1 in mice impacted expression of osteoblastic markers. In summary, there is definitive evidence supporting the relationship between FN1 and autosomal dominant SMDCF. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date 3/6/2024 (SOP Version 10).
Inheritance Pattern: AD
Disease ID:MONDO:0008479
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008479
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0008479
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0011165
Submitter: ClinGen
FN1 was first reported in relation to autosomal dominant Glomerulopathy with Fibronectin Deposits 2 (GFND2) in 2008 (Castelletti et al., PMID: 18268355). The condition has genetic heterogeneity and symptoms of proteinuria, microscopic hematuria, renal tubular acidosis, glomerular fibronectin deposits, edema, and high blood pressure that causes end-stage renal failure anywhere between ages 10 and 60 (but the disease may also be indolent). The gene is also associated with Spondylometaphyseal Dysplasia, Corner Fracture Type (SMDCF), which is autosomal dominant. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found clear differences in phenotypic variability between the two conditions. Therefore, the following disease entities have been split: GFND2 (OMIM #601894), SMDCF (OMIM #184255). The split curation for autosomal dominant SMDCF has been curated separately. 12 variants (missense, small in-frame deletions) that have been reported in over thirty probands in six publications (PMIDs: 18268355, 27056061, 30820325, 31419955, 35395622, 36774238) are included in this curation. The mechanism of pathogenicity is unclear. Some mutations appear have a loss-of-function effect (decreasing binding to heparin). However, another assay demonstrates that a mutation increases heparin binding, and an additional one demonstrates that a different mutation increases FN1 expression in kidney cells. This gene-disease relationship is also supported by experimental evidence (Humphrey's Lab Expression data) and interaction evidence (interaction with COL4A3 and COL4A4, which are both definitive for X-linked Alport Syndrome). In summary, there is moderate evidence supporting the relationship between FN1 and autosomal dominant GFND2. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Glomerulopathy GCEP on the meeting date 9/11/2023 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0008479
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0011165
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011165
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0008479
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007671
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011165
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Musculoskeletal; Renal
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FN1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_212482.4. 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 | 26 | 337 | 18 | 381 | ||
| missense | 9 | 18 | 870 | 179 | 5 | 1081 |
| nonsense | 1 | 18 | 19 | |||
| start loss | 0 | |||||
| frameshift | 2 | 20 | 22 | |||
| splice donor/acceptor (+/-2bp) | 2 | 1 | 23 | 1 | 27 | |
| Total | 11 | 22 | 957 | 517 | 23 | 1530 |
Highest pathogenic variant AF is 0.000011792073
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_997647.2 | 46 | MANE Select | |
| Ensembl | ENSP00000346839.4 | 46 | MANE Select | |
| RefSeq | NP_001293058.2 | 47 | Standard | |
| RefSeq | NP_001293059.2 | 45 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| fn1b | Danio rerio | Structure: atrioventricular valve Quality: morphology abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- ECM-receptor interaction - Homo sapiens (human)
- Focal adhesion - Homo sapiens (human)
- AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)
- Small cell lung cancer - Homo sapiens (human)
Biological Process
- angiogenesis
- regulation of protein phosphorylation
- platelet degranulation
- acute-phase response
- cell-substrate junction assembly
Molecular Function
- protease binding
- signaling receptor binding
- integrin binding
- extracellular matrix structural constituent
- protein binding
Cellular Component
- extracellular region
- fibrinogen complex
- basement membrane
- extracellular space
- endoplasmic reticulum lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000354785
- Coding exons
- 46
- Length
- 75733
- Individuals with no LoFs
- 125669
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 79
- Defined
- 125748
- p
- 0.000314
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.65 | 1196 | 1.37e+3 | 0.875 | 0.0000790 | 16072 |
| Missense (PolyPhen) | 519 | 699.87 | 0.74157 | 8402 | ||
| Synonymous | -0.582 | 541 | 524 | 1.03 | 0.0000328 | 4969 |
| Loss of Function | 8.00 | 34 | 134 | 0.254 | 0.00000770 | 1457 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00031 | 0.00031 | rare |
| Latino/Admixed American | 0.00046 | 0.00035 | rare |
| Ashkenazi Jewish | 0.00030 | 0.00030 | rare |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0.00028 | 0.00028 | rare |
| European (Non-Finnish) | 0.00033 | 0.00033 | rare |
| South Asian | 0.00039 | 0.00036 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Fibronectins bind cell surfaces and various compounds including collagen, fibrin, heparin, DNA, and actin. Fibronectins are involved in cell adhesion, cell motility, opsonization, wound healing, and maintenance of cell shape. Involved in osteoblast compaction through the fibronectin fibrillogenesis cell-mediated matrix assembly process, essential for osteoblast mineralization. Participates in the regulation of type I collagen deposition by osteoblasts.;
- Disease
- DISEASE: Glomerulopathy with fibronectin deposits 2 (GFND2) [MIM:601894]: Genetically heterogeneous autosomal dominant disorder characterized clinically by proteinuria, microscopic hematuria, and hypertension that leads to end-stage renal failure in the second to fifth decade of life. {ECO:0000269|PubMed:18268355}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spondylometaphyseal dysplasia, corner fracture type (SMDCF) [MIM:184255]: An autosomal dominant form of spondylometaphyseal dysplasia, a group of short stature disorders distinguished by abnormalities in the vertebrae and the metaphyses of the tubular bones. SMDCF is characterized by flake-like, triangular, or curvilinear ossification centers at the edges of irregular metaphyses that simulate fractures. These corner fractures involve the distal tibia, the ulnar aspect of the distal radius, the proximal humerus, and the proximal femur. They represent irregular ossification at the growth plates and secondary ossification centers. {ECO:0000269|PubMed:29100092}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.992
Intolerance Scores
- LoFtool
- 0.719
- RVIS EVS
- -2.32
- RVIS percentile EVS
- 1.19
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.698
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |