SPARC
protein-codingsecreted protein acidic and cysteine rich, the group of SPARC family
Gene summary
This gene encodes a cysteine-rich acidic matrix-associated protein. The encoded protein is required for the collagen in bone to become calcified but is also involved in extracellular matrix synthesis and promotion of changes to cell shape. The gene product has been associated with tumor suppression but has also been correlated with metastasis based on changes to cell shape which can promote tumor cell invasion. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2015]
- ON
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~25.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014672
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0014672
Submitter: Illumina
The SPARC gene is located on chromosome 5 at 5q33.1 and encodes the secreted protein acidic and cysteine rich, or osteonectin protein. SPARC was first reported in relation to autosomal recessive osteogenesis imperfecta in 2015 (26027498: Mendoza-Londono et al. 2015). Evidence supporting this gene-disease relationship includes limited case-level data and experimental data. Two unique homozygous missense variants in this gene were reported in two unrelated patients who showed repeated fractures, kyphoscoliosis, joint hyperlaxity, and underdeveloped muscles of the lower extremities, resulting in a clinical diagnosis of osteogenesis imperfecta type IV (26027498: Mendoza-Londono et al. 2015). Both variants were located in the calcium binding domain responsible for the binding of SPARC to collagen, and skin fibroblasts from both patients showed collagen abnormalities suggestive of a damaging effect of the variants. Neither the heterozygous parents of the patients nor heterozygous mutant mice showed a phenotype. Loss of function has been suggested as the mechanism of disease, but additional evidence is needed. This gene-disease relationship is supported by expression data, protein-interaction data, and mouse model data. The SPARC protein is highly expressed in osseous tissue with high turnover (26851678: Rosset and Bradshaw 2016) and interacts with various forms of collagen (745554: Sage et al. 1989). Homozygous SPARC null mice develop low-turnover osteopenia, cataracts, intervertebral disc degeneration, and increased adiposity (9524110: Gilmour et al. 1998; 10749571: Delany et al. 2000; 12721366: Bradshaw et al. 2003; 15879573: Gruber et al. 2005). 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.
Inheritance Pattern: AR
Disease ID:MONDO:0014672
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008148
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014672
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014672
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal; Ophthalmologic
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
Comments: Evidence for pathogenicity of the described variants is unclear
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SPARC variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003118.4. 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 | 3 | 71 | 1 | 75 | ||
| missense | 2 | 82 | 1 | 3 | 88 | |
| nonsense | 0 | |||||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 3 | 4 | |||
| Total | 4 | 0 | 89 | 72 | 4 | 169 |
Highest pathogenic variant AF is 0.0000024782564
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003109.1 | 9 | MANE Select | |
| Ensembl | ENSP00000231061.4 | 9 | MANE Select | |
| RefSeq | NP_001296372.1 | 9 | Standard | |
| RefSeq | NP_001296373.1 | 9 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| sparc | Danio rerio | Structure: blood cell Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- miR-targeted genes in muscle cell - TarBase
- miR-509-3p alteration of YAP1-ECM axis
- EMT transition in Colorectal Cancer
- Senescence and Autophagy in Cancer
- Vesicle-mediated transport
Biological Process
- ossification
- negative regulation of endothelial cell proliferation
- platelet degranulation
- receptor-mediated endocytosis
- heart development
Molecular Function
- extracellular matrix structural constituent
- calcium ion binding
- protein binding
- collagen binding
- extracellular matrix binding
Cellular Component
- extracellular region
- basement membrane
- extracellular space
- cytoplasm
- mitochondrion
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000231061
- Coding exons
- 9
- Length
- 26070
- Individuals with no LoFs
- 125740
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 6
- Defined
- 125746
- p
- 0.0000239
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.10 | 139 | 181 | 0.770 | 0.0000103 | 2017 |
| Missense (PolyPhen) | 60 | 80.758 | 0.74296 | 865 | ||
| Synonymous | 0.0379 | 74 | 74.4 | 0.994 | 0.00000470 | 551 |
| Loss of Function | 3.24 | 2 | 16.0 | 0.125 | 6.78e-7 | 192 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| 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) | 0.000026 | 0.000026 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Appears to regulate cell growth through interactions with the extracellular matrix and cytokines. Binds calcium and copper, several types of collagen, albumin, thrombospondin, PDGF and cell membranes. There are two calcium binding sites; an acidic domain that binds 5 to 8 Ca(2+) with a low affinity and an EF-hand loop that binds a Ca(2+) ion with a high affinity.;
- Disease
- DISEASE: Osteogenesis imperfecta 17 (OI17) [MIM:616507]: An autosomal recessive form of osteogenesis imperfecta, a connective tissue disorder characterized by low bone mass, bone fragility and susceptibility to fractures after minimal trauma. Disease severity ranges from very mild forms without fractures to intrauterine fractures and perinatal lethality. Extraskeletal manifestations, which affect a variable number of patients, are dentinogenesis imperfecta, hearing loss, and blue sclerae. {ECO:0000269|PubMed:26027498}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.765
Intolerance Scores
- LoFtool
- 0.256
- RVIS EVS
- 0.31
- RVIS percentile EVS
- 72.38
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.855
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |