NOTCH3
notch receptor 3, the group of Notch receptors|MicroRNA protein coding host genes
Basic information
Region (hg38): 19:15159038-15200995
Previous symbols: [ "CADASIL" ]
Links
Phenotypes
GenCC
Source:
- myofibromatosis, infantile, 2 (Limited), mode of inheritance: AD
- cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (Strong), mode of inheritance: AD
- cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (Definitive), mode of inheritance: AD
- cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (Supportive), mode of inheritance: AD
- lateral meningocele syndrome (Supportive), mode of inheritance: AD
- infantile myofibromatosis (Supportive), mode of inheritance: AD
- lateral meningocele syndrome (Strong), mode of inheritance: AD
- cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (Strong), mode of inheritance: AD
- pulmonary arterial hypertension (Disputed Evidence), mode of inheritance: AD
- cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (Moderate), mode of inheritance: AR
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (CADASIL1); Myofibromatosis, infantile 2 | AD | Cardiovascular; Oncologic | In Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (CADASIL1), certain agents (eg, angiography, anticoagulants, thrombolytic therapy) should be avoided; Myofibromatosis, infantile 2 involves benign tumors affecting the skin, muscle, bone, and viscera, and awareness of visceral neoplasms may be beneficial in order to diagnose and manage lesions | Cardiovascular; Craniofacial; Musculoskeletal; Neurologic; Oncologic | 7486874; 7564728; 7654071; 7500094; 8878478; 9188658; 9818928; 10371078; 12136071; 15096408; 15210914; 15313839; 15378071; 15666314; 16009764; 16263847; 15851739; 17135568; 16717210; 16864835; 18765654; 19174371; 20038773; 20301673; 21337686; 21671395; 22218279; 22996955; 23025651; 23696373; 23731542; 24000151; 25394726 |
ClinVar
This is a list of variants' phenotypes submitted to
- not_provided (1361 variants)
- Cerebral_arteriopathy,_autosomal_dominant,_with_subcortical_infarcts_and_leukoencephalopathy,_type_1 (343 variants)
- not_specified (225 variants)
- Inborn_genetic_diseases (204 variants)
- NOTCH3-related_disorder (121 variants)
- Lateral_meningocele_syndrome (86 variants)
- Myofibromatosis,_infantile,_2 (75 variants)
- Cerebral_arteriopathy_with_subcortical_infarcts_and_leukoencephalopathy (28 variants)
- See_cases (6 variants)
- Pulmonary_arterial_hypertension (5 variants)
- Migraine_with_aura (3 variants)
- Stroke_disorder (3 variants)
- Vascular_dementia (2 variants)
- Cerebral_arterial_disease (2 variants)
- Migraine (2 variants)
- Depression (2 variants)
- Abnormal_cerebral_white_matter_morphology (2 variants)
- Transient_ischemic_attack (2 variants)
- Ischemic_stroke (2 variants)
- CEREBRAL_ARTERIOPATHY,_AUTOSOMAL_RECESSIVE,_WITH_SUBCORTICAL_INFARCTS_AND_LEUKOENCEPHALOPATHY_1 (2 variants)
- Auditory_neuropathy (2 variants)
- Recurrent_subcortical_infarcts (1 variants)
- Breast_ductal_adenocarcinoma (1 variants)
- Prostate_cancer (1 variants)
- Cerebral_small_vessel_disease (1 variants)
- Atypical_behavior (1 variants)
- Cognitive_impairment (1 variants)
- Adult_onset_neurodegenerative_disorder (1 variants)
- Cerebral_arteriopathy_with_subcortical_infarcts_and_leukoencephalopathy_2 (1 variants)
- Abnormal_brain_morphology (1 variants)
- Sneddon_syndrome (1 variants)
- Myofibromatosis,_infantile,_1 (1 variants)
- Tension-type_headache (1 variants)
- Migraine_without_aura (1 variants)
- Progressive_psychomotor_deterioration (1 variants)
- Vascular_parkinsonism (1 variants)
- Cerebral_cavernous_malformation (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the NOTCH3 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000000435.3. 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 | 36 | 287 | 24 | 347 | ||
| missense | 127 | 165 | 653 | 170 | 1123 | |
| nonsense | 12 | 22 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 10 | 28 | 46 | |||
| splice donor/acceptor (+/-2bp) | 9 | |||||
| Total | 143 | 183 | 733 | 457 | 32 |
Highest pathogenic variant AF is 0.0000879734
Loading clinvar variants...
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| NOTCH3 | protein_coding | protein_coding | ENST00000263388 | 33 | 41349 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.408 | 0.592 | 125701 | 0 | 47 | 125748 | 0.000187 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 3.53 | 1037 | 1.41e+3 | 0.735 | 0.0000968 | 14774 |
| Missense in Polyphen | 360 | 619.85 | 0.58079 | 6597 | ||
| Synonymous | 1.51 | 557 | 604 | 0.922 | 0.0000454 | 4842 |
| Loss of Function | 7.09 | 22 | 97.6 | 0.226 | 0.00000514 | 1050 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000274 | 0.000266 |
| Ashkenazi Jewish | 0.000102 | 0.0000992 |
| East Asian | 0.000292 | 0.000272 |
| Finnish | 0.000146 | 0.000139 |
| European (Non-Finnish) | 0.000201 | 0.000193 |
| Middle Eastern | 0.000292 | 0.000272 |
| South Asian | 0.000268 | 0.000261 |
| Other | 0.000329 | 0.000163 |
dbNSFP
Source:
- Function
- FUNCTION: Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination (PubMed:15350543). Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs (By similarity). {ECO:0000250|UniProtKB:Q9R172, ECO:0000269|PubMed:15350543}.;
- Disease
- DISEASE: Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, 1 (CADASIL1) [MIM:125310]: A cerebrovascular disease characterized by multiple subcortical infarcts, pseudobulbar palsy, dementia, and the presence of granular deposits in small cerebral arteries producing ischemic stroke. {ECO:0000269|PubMed:10227618, ECO:0000269|PubMed:10371548, ECO:0000269|PubMed:10802807, ECO:0000269|PubMed:10854111, ECO:0000269|PubMed:11058919, ECO:0000269|PubMed:11102981, ECO:0000269|PubMed:11559313, ECO:0000269|PubMed:11755616, ECO:0000269|PubMed:11810186, ECO:0000269|PubMed:12136071, ECO:0000269|PubMed:12146805, ECO:0000269|PubMed:12589106, ECO:0000269|PubMed:12810003, ECO:0000269|PubMed:15229130, ECO:0000269|PubMed:15300988, ECO:0000269|PubMed:15350543, ECO:0000269|PubMed:15364702, ECO:0000269|PubMed:15378071, ECO:0000269|PubMed:15818833, ECO:0000269|PubMed:16009764, ECO:0000269|PubMed:24000151, ECO:0000269|PubMed:9388399}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myofibromatosis, infantile 2 (IMF2) [MIM:615293]: A rare mesenchymal disorder characterized by the development of benign tumors in the skin, striated muscles, bones, and, more rarely, visceral organs. Subcutaneous or soft tissue nodules commonly involve the skin of the head, neck, and trunk. Skeletal and muscular lesions occur in about half of the patients. Lesions may be solitary or multicentric, and they may be present at birth or become apparent in early infancy or occasionally in adult life. Visceral lesions are associated with high morbidity and mortality. {ECO:0000269|PubMed:23731542}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Lateral meningocele syndrome (LMNS) [MIM:130720]: A very rare skeletal disorder with facial anomalies, hypotonia and neurologic dysfunction due to meningocele, a protrusion of the meninges, unaccompanied by neural tissue, through a bony defect in the skull or vertebral column. LMNS facial features include hypertelorism and telecanthus, high arched eyebrows, ptosis, mid- facial hypoplasia, micrognathia, high and narrow palate, low-set ears and a hypotonic appearance. Additional variable features are connective tissue abnormalities, aortic dilation, a high-pitched nasal voice, wormian bones and osteolysis. {ECO:0000269|PubMed:25394726}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
- Pathway
- Breast cancer - Homo sapiens (human);Thyroid hormone signaling pathway - Homo sapiens (human);Apelin signaling pathway - Homo sapiens (human);Th1 and Th2 cell differentiation - Homo sapiens (human);MicroRNAs in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Notch signaling pathway - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);NOTCH-Core;Neural Crest Differentiation;Notch Signaling Pathway;Pre-NOTCH Expression and Processing;Canonical and Non-canonical Notch signaling;Role of Osx and miRNAs in tooth development;EMT transition in Colorectal Cancer;Notch Signaling Pathway;Notch Signaling Pathway;Notch;Signal Transduction;Gene expression (Transcription);Generic Transcription Pathway;RNA Polymerase II Transcription;Notch-HLH transcription pathway;Notch;NICD traffics to nucleus;Pre-NOTCH Transcription and Translation;Pre-NOTCH Processing in the Endoplasmic Reticulum;Pre-NOTCH Processing in Golgi;Pre-NOTCH Expression and Processing;Noncanonical activation of NOTCH3;NOTCH3 Activation and Transmission of Signal to the Nucleus;NOTCH3 Intracellular Domain Regulates Transcription;Signaling by NOTCH3;Signaling by NOTCH;Notch signaling pathway
(Consensus)
Recessive Scores
- pRec
- 0.197
Intolerance Scores
- loftool
- 0.0358
- rvis_EVS
- -1.29
- rvis_percentile_EVS
- 5.04
Haploinsufficiency Scores
- pHI
- 0.857
- hipred
- Y
- hipred_score
- 0.715
- ghis
- 0.597
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.870
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Notch3
- Phenotype
- growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype; vision/eye phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; normal 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); reproductive system phenotype; neoplasm; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; immune system phenotype; skeleton phenotype; renal/urinary system phenotype; hearing/vestibular/ear phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan);
Zebrafish Information Network
- Gene name
- notch3
- Affected structure
- caudal fin blood vessel
- Phenotype tag
- abnormal
- Phenotype quality
- displaced
Gene ontology
- Biological process
- negative regulation of transcription by RNA polymerase II;transcription initiation from RNA polymerase II promoter;Notch signaling pathway;positive regulation of transcription of Notch receptor target;forebrain development;negative regulation of neuron differentiation;negative regulation of Notch signaling pathway;positive regulation of smooth muscle cell proliferation;neuron fate commitment;artery morphogenesis;glomerular capillary formation
- Cellular component
- Golgi membrane;extracellular region;nucleoplasm;endoplasmic reticulum membrane;cytosol;plasma membrane;actin cytoskeleton;integral component of membrane;receptor complex
- Molecular function
- calcium ion binding;protein binding;enzyme binding;signaling receptor activity;identical protein binding;cadherin binding