SPRED1
protein-codingsprouty related EVH1 domain containing 1, the group of Protein phosphatase 1 regulatory subunits
Gene summary
The protein encoded by this gene is a member of the Sprouty family of proteins and is phosphorylated by tyrosine kinase in response to several growth factors. The encoded protein can act as a homodimer or as a heterodimer with SPRED2 to regulate activation of the MAP kinase cascade. Defects in this gene are a cause of neurofibromatosis type 1-like syndrome (NFLS). [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~104.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0012669
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0012669
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0012669
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0012669
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0012669
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0012669
Submitter: ClinGen
SPRED1 was first reported in relation to autosomal dominant Legius syndrome in 2007 (Brems et al., PMID 17704776). At least 63 variants (e.g. missense, in-frame indel, nonsense, 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 21 probands in 2 publications (PMIDs: 17704776, 21089071). Variants in this gene segregated with disease in 35 additional family members. The mechanism for disease is haploinsufficiency as demonstrated by patient variants and experimental evidence (PMIDs: 17704776, 27313208, 27503857). This gene-disease association is supported by a mouse model, functional alteration studies investigating heterologously expressed patient variants and coimmunoprecipitation assays with NF1, BRAF and KRAS. In summary SPRED1 is definitively associated with autosomal dominant Legius syndrome.
Inheritance Pattern: AD
Disease ID:MONDO:0012669
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Dermatologic; Musculoskeletal; Neurologic
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: Oncologic processes are reported in some individuals, but the overall risk is unclear, and it has been stated that the condition does not involve tumor predisposition
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SPRED1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_152594.3. 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 | 5 | 246 | 1 | 252 | ||
| missense | 1 | 6 | 572 | 61 | 2 | 642 |
| nonsense | 36 | 15 | 2 | 53 | ||
| start loss | 4 | 4 | ||||
| frameshift | 61 | 38 | 6 | 105 | ||
| splice donor/acceptor (+/-2bp) | 4 | 13 | 1 | 18 | ||
| Total | 102 | 76 | 586 | 307 | 3 | 1074 |
Highest pathogenic variant AF is 0.000016731983
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_689807.1 | 7 | MANE Select | |
| Ensembl | ENSP00000299084.4 | 7 | MANE Select | |
| Ensembl | ENSP00000453680.1 | 4 | Standard | |
| Ensembl | ENSP00000551439.1 | 8 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| spred1 | Danio rerio | Structure: thoracic duct Quality: hypoplastic abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- IL-5 Signaling Pathway
- Regulation of Microtubule Cytoskeleton
- Signal Transduction
- Signaling by FGFR
- Regulation of RAS by GAPs
Biological Process
- MAPK cascade
- inactivation of MAPK activity
- negative regulation of protein kinase activity
- fibroblast growth factor receptor signaling pathway
- negative regulation of peptidyl-threonine phosphorylation
Molecular Function
- stem cell factor receptor binding
- protein binding
- protein kinase binding
- phosphatase binding
- protein serine/threonine kinase inhibitor activity
Cellular Component
- nucleus
- cytosol
- plasma membrane
- caveola
- cytoplasmic vesicle
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000299084
- Coding exons
- 7
- Length
- 104924
- Individuals with no LoFs
- 125728
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 6
- Defined
- 125734
- p
- 0.0000239
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.17 | 194 | 246 | 0.790 | 0.0000134 | 2956 |
| Missense (PolyPhen) | 58 | 85.539 | 0.67805 | 1032 | ||
| Synonymous | 1.42 | 66 | 82.3 | 0.801 | 0.00000460 | 785 |
| Loss of Function | 4.00 | 3 | 24.3 | 0.123 | 0.00000165 | 270 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Tyrosine kinase substrate that inhibits growth-factor- mediated activation of MAP kinase. Negatively regulates hematopoiesis of bone marrow (By similarity). {ECO:0000250}.;
- Disease
- DISEASE: Neurofibromatosis 1-like syndrome (NFLS) [MIM:611431]: A disorder characterized mainly by cafe au lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1, axillary freckling, and macrocephaly. Additional clinical manifestations include Noonan-like facial dysmorphism, lipomas, learning disabilities and attention deficit-hyperactivity. {ECO:0000269|PubMed:17704776, ECO:0000269|PubMed:19443465, ECO:0000269|PubMed:20108422, ECO:0000269|PubMed:21089071}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.0921
Intolerance Scores
- LoFtool
- 0.250
- RVIS EVS
- -0.43
- RVIS percentile EVS
- 25.37
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.843
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |