ITGA3
protein-codingintegrin subunit alpha 3, the group of Integrin alpha subunits|CD molecules
Gene summary
The gene encodes a member of the integrin alpha chain family of proteins. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain that function as cell surface adhesion molecules. The encoded preproprotein is proteolytically processed to generate light and heavy chains that comprise the alpha 3 subunit. This subunit joins with a beta 1 subunit to form an integrin that interacts with extracellular matrix proteins including members of the laminin family. Expression of this gene may be correlated with breast cancer metastasis. [provided by RefSeq, Oct 2015]
- MSK18
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~34.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013881
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0013881
Submitter: ClinGen
The *ITGA3* gene is located on chromosome 17 at q21.33 and encodes the protein integrin alpha 3 which dimerizes with integrin beta 1 to form the α3β1 integrin duplex that functions as an adhesion molecule between the podocyte and glomerular basement membrane. *ITGA3* was first reported in relation to autosomal recessive 'interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa, congenital' in 2012 (Has et al., PMID: 22512483, OMIM:614748). The mechanism of pathogenicity is known to be loss of function. Interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa, congenital is characterized by significant protein loss in the urine, severe lung disease and/or blistering skin disease within the first months of life causing generalized edema, respiratory failure and/or skin/nail abnormalities. At least 10 variants (frameshift, splice, missense) have been reported in 10 probands in 9 publications (PMIDs: 22512483, 23114595, 25810266, 26854491, 32198874, 34023363, 34751145, 33768705 included in this curation). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached, considering case-level data. This gene-disease relationship is also supported by animal models, expression studies, in vitro functional assays, and rescue assays (PMIDs: 9211352, 30466509, 9151677, 8951069, 17015618, 19118220). In particular, ITGA3 knockout mice caused congenital epidermolysis bullosa-phenotype (PMID 9211352), abnormal nephrogenesis and abnormal lung morphogenesis (PMID 30466509). Transgenic mice with ITGA3 knockout isolated to the podocyte (2.5P-Cre; ITGA3fl /fl) developed nephrotic syndrome with severe proteinuria, focal segmental glomerulosclerosis and podocyte effacement (PMID 17015618). Transgenic mice with ITGA3 knockout isolated to the skin (K14-Cre; ITGA3fl /fl) developed severe skin defects recapitulating the epidermolysis bullosa-phenotype (PMID 19118220). In-vitro functional assays demonstrated increased fibronectin expression in skin, kidney and lung cells of a patient with *ITGA3* mutation and interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa, congenital (PMID 30466509). This was associated with an increased keratinocyte migratory phenotype (also seen in the K14-Cre; ITGA3fl /fl mouse), which could be rescued using by retroviral re-expression of ITGA3 (PMID 30466509). A total of 5.5/6 pts. for experimental evidence was reached. In summary, there is definitive evidence supporting the relationship between *ITGA3* and autosomal recessive interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa, congenital. 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:0013881
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0013881
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013881
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013881
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013881
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Dermatologic; Pulmonary; 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 ITGA3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002204.4. 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 | 8 | 111 | 1 | 120 | ||
| missense | 6 | 212 | 22 | 2 | 242 | |
| nonsense | 1 | 9 | 3 | 13 | ||
| start loss | 0 | |||||
| frameshift | 1 | 7 | 1 | 9 | ||
| splice donor/acceptor (+/-2bp) | 3 | 6 | 13 | 22 | ||
| Total | 5 | 28 | 237 | 133 | 3 | 406 |
Highest pathogenic variant AF is 0.000014596242
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002195.1 | 25 | MANE Select | |
| Ensembl | ENSP00000315190.8 | 25 | MANE Select | |
| Ensembl | ENSP00000007722.7 | 25 | Standard | |
| Ensembl | ENSP00000467851.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| itga3b | Danio rerio | Structure: melanocyte Quality: irregular spatial pattern 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)
- Dilated cardiomyopathy (DCM) - Homo sapiens (human)
- Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Homo sapiens (human)
Biological Process
- neuron migration
- cell-matrix adhesion
- integrin-mediated signaling pathway
- heart development
- memory
Molecular Function
- fibronectin binding
- protease binding
- integrin binding
- protein binding
- collagen binding
Cellular Component
- plasma membrane
- focal adhesion
- integrin complex
- external side of plasma membrane
- cell surface
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000007722
- Coding exons
- 25
- Length
- 34514
- Individuals with no LoFs
- 125691
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 57
- Defined
- 125748
- p
- 0.000227
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.36 | 469 | 637 | 0.737 | 0.0000387 | 6825 |
| Missense (PolyPhen) | 140 | 244.96 | 0.57153 | 2710 | ||
| Synonymous | 1.60 | 236 | 270 | 0.876 | 0.0000166 | 2191 |
| Loss of Function | 4.45 | 22 | 58.9 | 0.374 | 0.00000322 | 609 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00086 | 0.00086 | rare |
| Latino/Admixed American | 0.00041 | 0.00040 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0.000047 | 0.000046 | rare |
| European (Non-Finnish) | 0.00015 | 0.00015 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Integrin alpha-3/beta-1 is a receptor for fibronectin, laminin, collagen, epiligrin, thrombospondin and CSPG4. Integrin alpha-3/beta-1 provides a docking site for FAP (seprase) at invadopodia plasma membranes in a collagen-dependent manner and hence may participate in the adhesion, formation of invadopodia and matrix degradation processes, promoting cell invasion. Alpha- 3/beta-1 may mediate with LGALS3 the stimulation by CSPG4 of endothelial cells migration. {ECO:0000269|PubMed:10455171, ECO:0000269|PubMed:15181153}.;
- Disease
- DISEASE: Interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa, congenital (ILNEB) [MIM:614748]: A multiorgan disorder characterized by congenital nephrotic syndrome, interstitial lung disease, and epidermolysis bullosa. The respiratory and renal features predominate, and lung involvement accounts for the lethal course of the disease. {ECO:0000269|PubMed:22512483, ECO:0000269|PubMed:27717396}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.572
Intolerance Scores
- LoFtool
- 0.713
- RVIS EVS
- -0.88
- RVIS percentile EVS
- 10.56
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.804
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |