INPPL1
inositol polyphosphate phosphatase like 1, the group of SH2 domain containing|Phosphoinositide phosphatases|Sterile alpha motif domain containing
Basic information
Region (hg38): 11:72223701-72239147
Links
Phenotypes
GenCC
Source:
- opsismodysplasia (Definitive), mode of inheritance: AR
- opsismodysplasia (Strong), mode of inheritance: AR
- opsismodysplasia (Supportive), mode of inheritance: AR
- schneckenbecken dysplasia (Supportive), mode of inheritance: AR
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Opsismodysplasia | AR | Allergy/Immunology/Infectious; Cardiovascular; Pulmonary; Renal | The condition may involve renal phosphate wasting in some individuals, and prompt detection may allow beneficial dietary/medical management; Many individuals manifest with respiratory insufficiency and frequent respiratory infections, and awareness may allow prompt diagnosis and treatment; Individuals may also demonstrate congenital anomalies affecting the cardiovascular, renal, and other systems, and awareness may allow early detection and management | Allergy/Immunology/Infectious; Cardiovascular; Craniofacial; Musculoskeletal; Pulmonary; Renal | 12624139; 23273567; 23273569; 27708270 |
ClinVar
This is a list of variants' phenotypes submitted to
- not_provided (497 variants)
- Inborn_genetic_diseases (142 variants)
- Opsismodysplasia (46 variants)
- INPPL1-related_disorder (17 variants)
- not_specified (2 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the INPPL1 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000001567.4. Only rare variants are included in the table.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUSVUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 165 | 175 | ||||
| missense | 273 | 11 | 290 | |||
| nonsense | 7 | |||||
| start loss | 0 | |||||
| frameshift | 22 | |||||
| splice donor/acceptor (+/-2bp) | 11 | |||||
| Total | 19 | 18 | 286 | 176 | 6 |
Highest pathogenic variant AF is 0.000013115
Loading clinvar variants...
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| INPPL1 | protein_coding | protein_coding | ENST00000298229 | 28 | 15405 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.00233 | 0.998 | 125706 | 0 | 41 | 125747 | 0.000163 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 1.60 | 620 | 743 | 0.835 | 0.0000469 | 8057 |
| Missense in Polyphen | 134 | 231.1 | 0.57984 | 2682 | ||
| Synonymous | -0.652 | 320 | 306 | 1.05 | 0.0000186 | 2643 |
| Loss of Function | 5.17 | 17 | 60.3 | 0.282 | 0.00000290 | 696 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000182 | 0.000181 |
| Ashkenazi Jewish | 0.0000993 | 0.0000992 |
| East Asian | 0.000165 | 0.000163 |
| Finnish | 0.000232 | 0.000231 |
| European (Non-Finnish) | 0.000189 | 0.000185 |
| Middle Eastern | 0.000165 | 0.000163 |
| South Asian | 0.000164 | 0.000163 |
| Other | 0.000326 | 0.000326 |
dbNSFP
Source:
- Function
- FUNCTION: Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol- 3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively regulating the PI3K (phosphoinositide 3-kinase) pathways. Plays a central role in regulation of PI3K-dependent insulin signaling, although the precise molecular mechanisms and signaling pathways remain unclear. While overexpression reduces both insulin-stimulated MAP kinase and Akt activation, its absence does not affect insulin signaling or GLUT4 trafficking. Confers resistance to dietary obesity. May act by regulating AKT2, but not AKT1, phosphorylation at the plasma membrane. Part of a signaling pathway that regulates actin cytoskeleton remodeling. Required for the maintenance and dynamic remodeling of actin structures as well as in endocytosis, having a major impact on ligand-induced EGFR internalization and degradation. Participates in regulation of cortical and submembraneous actin by hydrolyzing PtdIns(3,4,5)P3 thereby regulating membrane ruffling (PubMed:21624956). Regulates cell adhesion and cell spreading. Required for HGF-mediated lamellipodium formation, cell scattering and spreading. Acts as a negative regulator of EPHA2 receptor endocytosis by inhibiting via PI3K-dependent Rac1 activation. Acts as a regulator of neuritogenesis by regulating PtdIns(3,4,5)P3 level and is required to form an initial protrusive pattern, and later, maintain proper neurite outgrowth. Acts as a negative regulator of the FC-gamma- RIIA receptor (FCGR2A). Mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), playing a central role in terminating signal transduction from activating immune/hematopoietic cell receptor systems. Involved in EGF signaling pathway. Upon stimulation by EGF, it is recruited by EGFR and dephosphorylates PtdIns(3,4,5)P3. Plays a negative role in regulating the PI3K-PKB pathway, possibly by inhibiting PKB activity. Down-regulates Fc-gamma-R-mediated phagocytosis in macrophages independently of INPP5D/SHIP1. In macrophages, down-regulates NF-kappa-B-dependent gene transcription by regulating macrophage colony-stimulating factor (M-CSF)-induced signaling. May also hydrolyze PtdIns(1,3,4,5)P4, and could thus affect the levels of the higher inositol polyphosphates like InsP6. Involved in endochondral ossification. {ECO:0000269|PubMed:11349134, ECO:0000269|PubMed:11739414, ECO:0000269|PubMed:12235291, ECO:0000269|PubMed:12676785, ECO:0000269|PubMed:12690104, ECO:0000269|PubMed:15668240, ECO:0000269|PubMed:17135240, ECO:0000269|PubMed:21624956, ECO:0000269|PubMed:23273569, ECO:0000269|PubMed:9660833}.;
- Disease
- DISEASE: Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:12086927, ECO:0000269|PubMed:15687335}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry.; DISEASE: Note=Genetic variations in INPPL1 may be a cause of susceptibility to metabolic syndrome. Metabolic syndrome is characterized by diabetes, insulin resistance, hypertension, and hypertriglyceridemia is absent. {ECO:0000269|PubMed:15220217, ECO:0000269|PubMed:17557929}.; DISEASE: Opsismodysplasia (OPSMD) [MIM:258480]: A rare skeletal dysplasia involving delayed bone maturation. Clinical signs observed at birth include short limbs, small hands and feet, relative macrocephaly with a large anterior fontanel, and characteristic craniofacial abnormalities including a prominent brow, depressed nasal bridge, a small anteverted nose, and a relatively long philtrum. Death secondary to respiratory failure during the first few years of life has been reported, but there can be long-term survival. Typical radiographic findings include shortened long bones with very delayed epiphyseal ossification, severe platyspondyly, metaphyseal cupping, and characteristic abnormalities of the metacarpals and phalanges. {ECO:0000269|PubMed:23273569}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
- Pathway
- B cell receptor signaling pathway - Homo sapiens (human);Fc gamma R-mediated phagocytosis - Homo sapiens (human);Inositol phosphate metabolism - Homo sapiens (human);Phosphatidylinositol signaling system - Homo sapiens (human);Insulin signaling pathway - Homo sapiens (human);EGF-Ncore;EGF-EGFR Signaling Pathway;Insulin Signaling;D-<i>myo</i>-inositol (1,3,4)-trisphosphate biosynthesis;superpathway of D-<i>myo</i>-inositol (1,4,5)-trisphosphate metabolism;Signaling by Interleukins;skeletal muscle hypertrophy is regulated via akt-mtor pathway;Metabolism of lipids;Cytokine Signaling in Immune system;1D-<i>myo</i>-inositol hexakisphosphate biosynthesis II (mammalian);Inositol phosphate metabolism;3-phosphoinositide degradation;D-<i>myo</i>-inositol (1,4,5)-trisphosphate degradation;Immune System;Metabolism;Interleukin receptor SHC signaling;Interleukin-2 family signaling;superpathway of inositol phosphate compounds;Fibroblast growth factor-1;EGFR1;Synthesis of IP3 and IP4 in the cytosol;Inositol phosphate metabolism;Synthesis of PIPs at the plasma membrane;Class I PI3K signaling events;PI Metabolism;Phospholipid metabolism;Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met);EPHA2 forward signaling;Interleukin-3, 5 and GM-CSF signaling
(Consensus)
Recessive Scores
- pRec
- 0.247
Intolerance Scores
- loftool
- 0.0895
- rvis_EVS
- -1.63
- rvis_percentile_EVS
- 2.84
Haploinsufficiency Scores
- pHI
- 0.122
- hipred
- Y
- hipred_score
- 0.715
- ghis
- 0.553
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.999
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Inppl1
- Phenotype
- growth/size/body region phenotype; craniofacial phenotype; homeostasis/metabolism phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span);
Zebrafish Information Network
- Gene name
- inppl1a
- Affected structure
- whole organism
- Phenotype tag
- abnormal
- Phenotype quality
- wholly dorsalized
Gene ontology
- Biological process
- endochondral ossification;immune system process;glucose metabolic process;phosphatidylinositol biosynthetic process;endocytosis;actin filament organization;cell adhesion;negative regulation of cell population proliferation;post-embryonic development;negative regulation of gene expression;cytokine-mediated signaling pathway;response to insulin;inositol phosphate metabolic process;phosphatidylinositol dephosphorylation;ruffle assembly
- Cellular component
- Golgi apparatus;cytosol;cytoskeleton;plasma membrane;lamellipodium;filopodium
- Molecular function
- actin binding;protein binding;SH3 domain binding;phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity;SH2 domain binding;inositol-1,3,4,5-tetrakisphosphate 5-phosphatase activity