NRAS
NRAS proto-oncogene, GTPase, the group of RAS type GTPase family
Basic information
Region (hg38): 1:114704469-114716771
Links
Phenotypes
GenCC
Source:
- Noonan syndrome 6 (Definitive), mode of inheritance: AD
- Noonan syndrome 6 (Definitive), mode of inheritance: AD
- Noonan syndrome 6 (Strong), mode of inheritance: AD
- Noonan syndrome 6 (Strong), mode of inheritance: AD
- cardiofaciocutaneous syndrome (Strong), mode of inheritance: AD
- Noonan syndrome (Supportive), mode of inheritance: AD
- Costello syndrome (Limited), mode of inheritance: AD
- Noonan syndrome (Definitive), mode of inheritance: AD
- cardiofaciocutaneous syndrome (Limited), mode of inheritance: AD
- Noonan syndrome with multiple lentigines (Limited), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Autoimmune lymphoproliferative syndrome type IV; Noonan syndrome 6 | AD | Cardiovascular; Oncologic | The condition may also include cardiac anomalies and dysrhythmias, and appropriate care may be beneficial; Individuals with Autoimmune lymphoproliferative syndrome type IV may be at risk of hematologic malignancies, and individuals with Noonan syndrome 6 have been described with juvenile myelomonocytic leukemia such that surveillance/early treatment may reduce morbidity | Cardiovascular; Craniofacial; Dermatologic; Genitourinary; Musculoskeletal; Neurologic; Oncologic | 17517660; 19775298; 19966803; 20301303; 21901340; 22855653; 22887781 |
ClinVar
This is a list of variants' phenotypes submitted to
- not provided (6 variants)
- Noonan syndrome 6 (5 variants)
- Malignant neoplasm of body of uterus (4 variants)
- Multiple myeloma (4 variants)
- RASopathy (4 variants)
- Neoplasm of the large intestine (4 variants)
- Melanoma (4 variants)
- Non-small cell lung carcinoma (4 variants)
- Gastric adenocarcinoma (4 variants)
- Acute myeloid leukemia (4 variants)
- Malignant melanoma of skin (4 variants)
- Noonan syndrome 1 (3 variants)
- Myelodysplastic syndrome (3 variants)
- Chronic myelogenous leukemia, BCR-ABL1 positive (2 variants)
- Adrenal cortex carcinoma (1 variants)
- Transitional cell carcinoma of the bladder (1 variants)
- Ovarian serous cystadenocarcinoma (1 variants)
- Papillary renal cell carcinoma type 1 (1 variants)
- Glioblastoma (1 variants)
- B-cell chronic lymphocytic leukemia (1 variants)
- Hepatocellular carcinoma (1 variants)
- Lung adenocarcinoma (1 variants)
- Increased nuchal translucency (1 variants)
- NRAS-related disorder (1 variants)
- Neoplasm of brain (1 variants)
- Noonan syndrome (1 variants)
- Juvenile myelomonocytic leukemia;Noonan syndrome (1 variants)
- Noonan syndrome and Noonan-related syndrome (1 variants)
- Thyroid tumor (1 variants)
- Nasopharyngeal neoplasm (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the NRAS gene is commonly pathogenic or not.
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.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 35 | 35 | ||||
| missense | 11 | 68 | 86 | |||
| nonsense | 3 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| inframe indel | 4 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| splice region | 5 | 7 | 12 | |||
| non coding | 44 | 41 | 19 | 104 | ||
| Total | 8 | 12 | 117 | 76 | 19 |
Highest pathogenic variant AF is 0.00000658
Variants in NRAS
This is a list of pathogenic ClinVar variants found in the NRAS region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 1-114704594-C-T | Noonan syndrome 6 | Likely benign (Jan 12, 2018) | ||
| 1-114704595-G-A | Noonan syndrome 6 | Likely benign (Jan 13, 2018) | ||
| 1-114704664-A-T | Noonan syndrome 6 | Uncertain significance (Jan 12, 2018) | ||
| 1-114704690-A-G | Noonan syndrome 6 | Uncertain significance (Jan 13, 2018) | ||
| 1-114704702-A-G | Noonan syndrome 6 | Uncertain significance (Jan 13, 2018) | ||
| 1-114704709-C-T | Benign (Sep 01, 2022) | |||
| 1-114704710-G-A | Noonan syndrome 6 | Benign (Jan 13, 2018) | ||
| 1-114704728-C-A | Noonan syndrome 6 | Likely benign (Jan 13, 2018) | ||
| 1-114704732-A-G | Noonan syndrome 6 | Uncertain significance (Jan 12, 2018) | ||
| 1-114704753-T-A | Noonan syndrome 6 | Uncertain significance (Jan 13, 2018) | ||
| 1-114704788-T-C | Noonan syndrome 6 | Likely benign (Jan 13, 2018) | ||
| 1-114704875-G-C | Noonan syndrome 6 | Likely benign (Jan 12, 2018) | ||
| 1-114704991-C-A | Noonan syndrome 6 | Uncertain significance (Jan 12, 2018) | ||
| 1-114705032-G-A | Noonan syndrome 6 | Uncertain significance (Jan 13, 2018) | ||
| 1-114705074-T-C | Noonan syndrome 6 | Uncertain significance (Jan 13, 2018) | ||
| 1-114705128-TA-T | Noonan syndrome | Likely benign (Jun 14, 2016) | ||
| 1-114705234-C-T | Noonan syndrome 6 | Uncertain significance (Jan 12, 2018) | ||
| 1-114705250-A-T | Noonan syndrome 6 | Uncertain significance (Jan 13, 2018) | ||
| 1-114705278-A-G | Noonan syndrome 6 | Likely benign (Jan 13, 2018) | ||
| 1-114705283-G-T | Noonan syndrome 6 | Uncertain significance (Jan 12, 2018) | ||
| 1-114705289-A-G | Noonan syndrome 6 | Conflicting classifications of pathogenicity (Jan 01, 2023) | ||
| 1-114705310-A-T | Noonan syndrome 6 | Likely benign (Jan 13, 2018) | ||
| 1-114705327-G-A | Noonan syndrome 6 | Uncertain significance (Jan 12, 2018) | ||
| 1-114705380-C-A | Noonan syndrome 6 | Uncertain significance (Jan 12, 2018) | ||
| 1-114705417-T-A | Noonan syndrome 6 | Uncertain significance (Jan 12, 2018) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| NRAS | protein_coding | protein_coding | ENST00000369535 | 4 | 12426 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.490 | 0.506 | 125744 | 0 | 4 | 125748 | 0.0000159 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 1.71 | 55 | 104 | 0.528 | 0.00000520 | 1247 |
| Missense in Polyphen | 8 | 28.786 | 0.27791 | 385 | ||
| Synonymous | 0.0111 | 39 | 39.1 | 0.998 | 0.00000219 | 355 |
| Loss of Function | 2.39 | 2 | 10.3 | 0.194 | 6.06e-7 | 112 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.0000615 | 0.0000615 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.00 | 0.00 |
| Finnish | 0.00 | 0.00 |
| European (Non-Finnish) | 0.0000264 | 0.0000264 |
| Middle Eastern | 0.00 | 0.00 |
| South Asian | 0.00 | 0.00 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.;
- Disease
- DISEASE: Leukemia, juvenile myelomonocytic (JMML) [MIM:607785]: An aggressive pediatric myelodysplastic syndrome/myeloproliferative disorder characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny. Patients have splenomegaly, enlarged lymph nodes, rashes, and hemorrhages. {ECO:0000269|PubMed:17332249}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Noonan syndrome 6 (NS6) [MIM:613224]: A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. {ECO:0000269|PubMed:19966803}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: RAS-associated autoimmune leukoproliferative disorder (RALD) [MIM:614470]: A disorder of apoptosis, characterized by chronic accumulation of non-malignant lymphocytes, defective lymphocyte apoptosis, and an increased risk for the development of hematologic malignancies. {ECO:0000269|PubMed:17517660}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Melanocytic nevus syndrome, congenital (CMNS) [MIM:137550]: A syndrome characterized by congenital pigmentary skin lesions which can occur at any site and can cover most of the body surface. These lesions may or may not be hairy. Congenital melanocytic nevi are associated with neuromelanosis (the presence of melanin-producing cells within the brain parenchyma or leptomeninges). Less commonly they are associated with malignant melanoma in childhood, both in the skin and the central nervous system. CMNS patients also tend to have a characteristic facial appearance, including wide or prominent forehead, periorbital fullness, small short nose with narrow nasal bridge, round face, full cheeks, prominent premaxilla, and everted lower lip. {ECO:0000269|PubMed:18633438, ECO:0000269|PubMed:23392294}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Melanosis, neurocutaneous (NCMS) [MIM:249400]: A rare congenital disease characterized by the presence of giant or multiple melanocytic nevi on the skin, foci of melanin-producing cells within the brain parenchyma, and infiltration of leptomeninges by abnormal melanin deposits. Neurologic abnormalities include seizures, hydrocephalus, arachnoid cysts, tumors, and syringomyelia. Some patients may develop malignant melanoma. {ECO:0000269|PubMed:23392294}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Keratinocytic non-epidermolytic nevus (KNEN) [MIM:162900]: Epidermal nevi of the common, non-organoid and non- epidermolytic type are benign skin lesions and may vary in their extent from a single (usually linear) lesion to widespread and systematized involvement. They may be present at birth or develop early during childhood. {ECO:0000269|PubMed:22499344}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Thyroid cancer, non-medullary, 2 (NMTC2) [MIM:188470]: A form of non-medullary thyroid cancer (NMTC), a cancer characterized by tumors originating from the thyroid follicular cells. NMTCs represent approximately 95% of all cases of thyroid cancer and are classified into papillary, follicular, Hurthle cell, and anaplastic neoplasms. {ECO:0000269|PubMed:12727991}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
- Pathway
- PI3K-Akt signaling pathway - Homo sapiens (human);Non-small cell lung cancer - Homo sapiens (human);Chronic myeloid leukemia - Homo sapiens (human);Gastric cancer - Homo sapiens (human);mTOR signaling pathway - Homo sapiens (human);Relaxin signaling pathway - Homo sapiens (human);Oxytocin signaling pathway - Homo sapiens (human);T cell receptor signaling pathway - Homo sapiens (human);B cell receptor signaling pathway - Homo sapiens (human);Fc epsilon RI signaling pathway - Homo sapiens (human);Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human);Renal cell carcinoma - Homo sapiens (human);VEGF signaling pathway - Homo sapiens (human);Long-term potentiation - Homo sapiens (human);Neurotrophin signaling pathway - Homo sapiens (human);Central carbon metabolism in cancer - Homo sapiens (human);Choline metabolism in cancer - Homo sapiens (human);Serotonergic synapse - Homo sapiens (human);Melanoma - Homo sapiens (human);AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human);Bladder cancer - Homo sapiens (human);Longevity regulating pathway - multiple species - Homo sapiens (human);Long-term depression - Homo sapiens (human);Acute myeloid leukemia - Homo sapiens (human);GnRH signaling pathway - Homo sapiens (human);Breast cancer - Homo sapiens (human);ErbB signaling pathway - Homo sapiens (human);Autophagy - animal - Homo sapiens (human);Gap junction - Homo sapiens (human);FoxO signaling pathway - Homo sapiens (human);Chemokine signaling pathway - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);Regulation of actin cytoskeleton - Homo sapiens (human);Mitophagy - animal - Homo sapiens (human);Axon guidance - Homo sapiens (human);Thermogenesis - Homo sapiens (human);Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human);Hepatocellular carcinoma - Homo sapiens (human);Glioma - Homo sapiens (human);Thyroid hormone signaling pathway - Homo sapiens (human);Prostate cancer - Homo sapiens (human);Longevity regulating pathway - Homo sapiens (human);Apelin signaling pathway - Homo sapiens (human);Estrogen signaling pathway - Homo sapiens (human);C-type lectin receptor signaling pathway - Homo sapiens (human);Rap1 signaling pathway - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Natural killer cell mediated cytotoxicity - Homo sapiens (human);Sphingolipid signaling pathway - Homo sapiens (human);Phospholipase D signaling pathway - Homo sapiens (human);Proteoglycans in cancer - Homo sapiens (human);Prolactin signaling pathway - Homo sapiens (human);MicroRNAs in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Viral carcinogenesis - Homo sapiens (human);Hepatitis C - Homo sapiens (human);Hepatitis B - Homo sapiens (human);Apoptosis - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Cholinergic synapse - Homo sapiens (human);Thyroid cancer - Homo sapiens (human);Endometrial cancer - Homo sapiens (human);Colorectal cancer - Homo sapiens (human);Alcoholism - Homo sapiens (human);Insulin signaling pathway - Homo sapiens (human);Melanogenesis - Homo sapiens (human);EGFR Inhibitor Pathway, Pharmacodynamics;Human papillomavirus infection - Homo sapiens (human);Bisphosphonate Pathway, Pharmacodynamics;Pathway_PA165959425;Sorafenib Pharmacodynamics;Vemurafenib Pathway, Pharmacodynamics;update your name in edit mode;VEGF Signaling Pathway;Fc Epsilon Receptor I Signaling in Mast Cells;EGF-Core;Signaling Pathways in Glioblastoma;RalA downstream regulated genes;TNF alpha Signaling Pathway;Aryl Hydrocarbon Receptor;Extracellular vesicle-mediated signaling in recipient cells;Rac1-Pak1-p38-MMP-2 pathway;G Protein Signaling Pathways;BDNF-TrkB Signaling;MAPK Signaling Pathway;PI3K-AKT-mTOR signaling pathway and therapeutic opportunities;Chemokine signaling pathway;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;Endometrial cancer;PI3K-Akt Signaling Pathway;MET in type 1 papillary renal cell carcinoma;MAPK Cascade;Ras Signaling;Regulation of Actin Cytoskeleton;DNA Damage Response (only ATM dependent);Serotonin Receptor 2 and ELK-SRF-GATA4 signaling;SHC1 events in ERBB2 signaling;Developmental Biology;Signaling by PTK6;Signaling by GPCR;FRS-mediated FGFR2 signaling;Signaling by FGFR2;Regulation of Ras family activation;MAP2K and MAPK activation;SHC-mediated cascade:FGFR2;FRS-mediated FGFR3 signaling;Downstream signaling of activated FGFR2;RAF activation;SHC-mediated cascade:FGFR3;Neutrophil degranulation;Downstream signaling of activated FGFR3;Disease;Signaling by FGFR3;Signal Transduction;FRS-mediated FGFR4 signaling;SHC-mediated cascade:FGFR4;Downstream signaling of activated FGFR4;DAP12 signaling;DAP12 interactions;Signaling by FGFR4;Signaling by FGFR;VEGFA-VEGFR2 Pathway;B cell receptor signaling;SOS-mediated signalling;IRS-mediated signalling;Insulin receptor signalling cascade;Signaling by Insulin receptor;Activation of RAS in B cells;Signaling by the B Cell Receptor (BCR);SHC1 events in EGFR signaling;Signaling by PDGF;CD4 T cell receptor signaling-ERK cascade;CD209 (DC-SIGN) signaling;C-type lectin receptors (CLRs);HGF;FCERI mediated MAPK activation;Fc epsilon receptor (FCERI) signaling;IGF signaling;Innate Immune System;Immune System;Regulation of RAS by GAPs;FGF;Signaling by FGFR2 in disease;Adaptive Immune System;insulin Mam;Downstream signaling events of B Cell Receptor (BCR);Signaling by EGFR;p38MAPK events;Signalling to RAS;Signalling to ERKs;Signaling by NTRK1 (TRKA);Integrin;Activated NTRK2 signals through RAS;Signaling by NTRK2 (TRKB);Signaling by NTRKs;SHP2 signaling;Tie2 Signaling;Ras signaling in the CD4+ TCR pathway;ErbB1 downstream signaling;Cell surface interactions at the vascular wall;Hemostasis;Negative regulation of MAPK pathway;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;JAK STAT pathway and regulation;PDGF;GRB2 events in ERBB2 signaling;EGFR Transactivation by Gastrin;NCAM signaling for neurite out-growth;NGF;PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases;Signaling by Non-Receptor Tyrosine Kinases;MAP kinase cascade;C-MYB transcription factor network;IL2-mediated signaling events;Downstream signal transduction;Class I PI3K signaling events;Signaling by EGFRvIII in Cancer;Signaling by EGFR in Cancer;Signaling by VEGF;GRB2 events in EGFR signaling;Signaling by FGFR3 point mutants in cancer;Signaling by FGFR4 in disease;Axon guidance;Signaling by FGFR3 fusions in cancer;Signaling by FGFR3 in disease;Signaling by SCF-KIT;Signaling by FGFR in disease;Signaling by ERBB2;SHC1 events in ERBB4 signaling;Signaling by ERBB4;SHC-related events triggered by IGF1R;IRS-related events triggered by IGF1R;IGF1R signaling cascade;MET activates RAS signaling;Signaling by FGFR1 in disease;Signaling by MET;Constitutive Signaling by EGFRvIII;Signaling by Receptor Tyrosine Kinases;Signaling by RAS mutants;Signaling by high-kinase activity BRAF mutants;Gastrin-CREB signalling pathway via PKC and MAPK;G alpha (q) signalling events;GPCR downstream signalling;Signaling by moderate kinase activity BRAF mutants;Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants;Signaling by Ligand-Responsive EGFR Variants in Cancer;EGF;Paradoxical activation of RAF signaling by kinase inactive BRAF;ErbB2/ErbB3 signaling events;GMCSF-mediated signaling events;mTOR signaling pathway;Neurotrophic factor-mediated Trk receptor signaling;Signaling by BRAF and RAF fusions;Oncogenic MAPK signaling;Diseases of signal transduction;Downstream signaling in naïve CD8+ T cells;Internalization of ErbB1;TCR signaling in naïve CD8+ T cells;CXCR3-mediated signaling events;EPHB forward signaling;Plasma membrane estrogen receptor signaling;Trk receptor signaling mediated by PI3K and PLC-gamma;PDGFR-beta signaling pathway;Downstream signaling of activated FGFR1;Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R);Trk receptor signaling mediated by the MAPK pathway;TCR signaling in naïve CD4+ T cells;FRS-mediated FGFR1 signaling;SHC-mediated cascade:FGFR1;insulin;VEGFR2 mediated cell proliferation;Signaling by FGFR1;CD4 T cell receptor signaling
(Consensus)
Recessive Scores
- pRec
- 0.124
Intolerance Scores
- loftool
- rvis_EVS
- 0.01
- rvis_percentile_EVS
- 54.63
Haploinsufficiency Scores
- pHI
- 1.00
- hipred
- Y
- hipred_score
- 0.783
- ghis
- 0.711
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.988
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Low | Low |
| Primary Immunodeficiency | Medium | Low | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Nras
- Phenotype
- embryo phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); 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); normal phenotype; hematopoietic system 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); neoplasm; pigmentation phenotype; limbs/digits/tail phenotype; vision/eye phenotype; immune system phenotype; skeleton 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); growth/size/body region phenotype; endocrine/exocrine gland phenotype; craniofacial phenotype; cellular phenotype; homeostasis/metabolism phenotype;
Gene ontology
- Biological process
- MAPK cascade;positive regulation of endothelial cell proliferation;stimulatory C-type lectin receptor signaling pathway;Ras protein signal transduction;neutrophil degranulation
- Cellular component
- Golgi membrane;Golgi apparatus;plasma membrane;membrane;extracellular exosome;tertiary granule membrane
- Molecular function
- GTPase activity;protein binding;GTP binding;protein-containing complex binding