BRAF
B-Raf proto-oncogene, serine/threonine kinase, the group of RAF family|Mitogen-activated protein kinase kinase kinases
Basic information
Region (hg38): 7:140719327-140924929
Links
Phenotypes
GenCC
Source:
- Noonan syndrome 7 (Definitive), mode of inheritance: AD
- cardiofaciocutaneous syndrome 1 (Definitive), mode of inheritance: AD
- cardiofaciocutaneous syndrome 1 (Definitive), mode of inheritance: AD
- Noonan syndrome 7 (Moderate), mode of inheritance: AD
- LEOPARD syndrome 3 (Limited), mode of inheritance: AD
- cardiofaciocutaneous syndrome 1 (Definitive), mode of inheritance: AD
- LEOPARD syndrome 3 (Strong), mode of inheritance: AD
- cardiofaciocutaneous syndrome 1 (Strong), mode of inheritance: AD
- Noonan syndrome 7 (Strong), mode of inheritance: AD
- Noonan syndrome with multiple lentigines (Supportive), mode of inheritance: AD
- cardiofaciocutaneous syndrome (Supportive), mode of inheritance: AD
- anaplastic astrocytoma (Limited), mode of inheritance: AD
- LEOPARD syndrome 3 (Definitive), mode of inheritance: AD
- Noonan syndrome 7 (Definitive), mode of inheritance: AD
- cardiofaciocutaneous syndrome 1 (Strong), mode of inheritance: AD
- LEOPARD syndrome 3 (Strong), mode of inheritance: AD
- Noonan syndrome 7 (Strong), mode of inheritance: AD
- Noonan syndrome (Moderate), mode of inheritance: AD
- Noonan syndrome with multiple lentigines (Limited), mode of inheritance: AD
- cardiofaciocutaneous syndrome (Definitive), mode of inheritance: AD
- Costello syndrome (Disputed Evidence), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Noonan syndrome 7; Cardiofaciocutaneous syndrome 1; LEOPARD syndrome 3 | AD | Cardiovascular; Hematologic; Oncologic | Surveillance and treatment related tomanifestations such as cardiac anomalies (which include pulmonic stenosis, hypertrophic cardiomyopathy, and arrhythmias) can be beneficial; The disorders can include bleeding diathesis, and recognition and preventive measures (eg, in surgical situations) can be beneficial; Individuals with malignancies (eg, ALL) have been reported, and awareness of increased risk may be beneficial | Cardiovascular; Craniofacial; Dermatologic; Genitourinary; Hematologic; Musculoskeletal; Neurologic; Oncologic; Ophthalmologic; | 16474404; 16439621; 17551924; 17483702; 19047498; 18456719; 18042262; 18413255; 19206169; 20301303; 20301365; 20523244; 21349766; 21495173; 22946697 |
| The conditions may be frequently clinically recognized due to characteristic facial features as well as other manifestations |
ClinVar
This is a list of variants' phenotypes submitted to
- not provided (36 variants)
- RASopathy (28 variants)
- Cardio-facio-cutaneous syndrome (19 variants)
- Cardiofaciocutaneous syndrome 1 (14 variants)
- Melanoma (9 variants)
- Noonan syndrome 7 (8 variants)
- Noonan syndrome 1 (8 variants)
- Noonan syndrome (7 variants)
- Noonan syndrome and Noonan-related syndrome (7 variants)
- Neoplasm (7 variants)
- Lung adenocarcinoma (6 variants)
- Noonan syndrome;Cardio-facio-cutaneous syndrome (6 variants)
- Prostate adenocarcinoma (5 variants)
- Malignant melanoma of skin (5 variants)
- Transitional cell carcinoma of the bladder (4 variants)
- Multiple myeloma (4 variants)
- Neoplasm of the large intestine (4 variants)
- Non-small cell lung carcinoma (4 variants)
- Squamous cell carcinoma of the skin (3 variants)
- B-cell chronic lymphocytic leukemia (3 variants)
- Inborn genetic diseases (3 variants)
- Cardiovascular phenotype (3 variants)
- Squamous cell lung carcinoma (3 variants)
- Malignant neoplasm of body of uterus (2 variants)
- Carcinoma of colon (2 variants)
- Lung carcinoma (2 variants)
- Gastric adenocarcinoma (2 variants)
- Thyroid tumor (2 variants)
- LEOPARD syndrome 3 (2 variants)
- Cardio-facio-cutaneous syndrome;Noonan syndrome (2 variants)
- BRAF-related disorder (1 variants)
- Thyroid cancer, nonmedullary, 2 (1 variants)
- Cardiofaciocutaneous syndrome 1;LEOPARD syndrome 3;Noonan syndrome 7 (1 variants)
- not specified (1 variants)
- Neoplasm of the large intestine;Non-small cell lung carcinoma (1 variants)
- Colorectal cancer (1 variants)
- Glioblastoma (1 variants)
- Neurodevelopmental delay (1 variants)
- Noonan syndrome with multiple lentigines (1 variants)
- Noonan syndrome 1;Cardiofaciocutaneous syndrome 1 (1 variants)
- Prostate cancer, hereditary, 1 (1 variants)
- Hypertrophic cardiomyopathy 4 (1 variants)
- Non-Hodgkin lymphoma (1 variants)
- Childhood ganglioglioma (1 variants)
- 6 conditions (1 variants)
- Lung carcinoma;Noonan syndrome 1;Noonan syndrome 7;Cardiofaciocutaneous syndrome 1;LEOPARD syndrome 3 (1 variants)
- Ataxia-telangiectasia syndrome (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the BRAF 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 | 198 | 11 | 211 | |||
| missense | 44 | 60 | 321 | 436 | ||
| nonsense | 5 | |||||
| start loss | 0 | |||||
| frameshift | 8 | |||||
| inframe indel | 15 | |||||
| splice donor/acceptor (+/-2bp) | 5 | |||||
| splice region | 28 | 36 | 1 | 65 | ||
| non coding | 16 | 205 | 86 | 307 | ||
| Total | 46 | 64 | 365 | 411 | 101 |
Variants in BRAF
This is a list of pathogenic ClinVar variants found in the BRAF region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 7-140726370-G-A | Likely benign (Jun 01, 2023) | |||
| 7-140734210-C-T | Noonan syndrome 7 • LEOPARD syndrome 3 | Benign (Jan 13, 2018) | ||
| 7-140734381-A-G | Noonan syndrome 7 • LEOPARD syndrome 3 | Uncertain significance (Jan 12, 2018) | ||
| 7-140734394-T-C | Noonan syndrome 7 • LEOPARD syndrome 3 | Uncertain significance (Jan 12, 2018) | ||
| 7-140734454-T-C | Noonan syndrome 7 • LEOPARD syndrome 3 | Uncertain significance (Jan 13, 2018) | ||
| 7-140734473-C-G | LEOPARD syndrome 3 • Noonan syndrome 7 | Uncertain significance (Jan 13, 2018) | ||
| 7-140734486-G-A | LEOPARD syndrome 3 • Noonan syndrome 7 | Benign/Likely benign (Jan 12, 2018) | ||
| 7-140734590-A-G | not specified • Noonan syndrome 7 • LEOPARD syndrome 3 • RASopathy | Likely benign (Jan 31, 2020) | ||
| 7-140734594-G-A | Noonan syndrome 7 • LEOPARD syndrome 3 | Uncertain significance (Jan 13, 2018) | ||
| 7-140734597-T-C | Uncertain significance (Sep 26, 2023) | |||
| 7-140734599-AGTG-A | RASopathy | Uncertain significance (Sep 14, 2022) | ||
| 7-140734602-G-A | RASopathy | Uncertain significance (May 19, 2023) | ||
| 7-140734605-C-G | RASopathy | Uncertain significance (Nov 27, 2021) | ||
| 7-140734607-G-A | RASopathy | Uncertain significance (May 27, 2022) | ||
| 7-140734608-G-A | Uncertain significance (Feb 01, 2023) | |||
| 7-140734613-G-A | RASopathy | Uncertain significance (Apr 28, 2023) | ||
| 7-140734619-T-C | RASopathy | Uncertain significance (Oct 07, 2022) | ||
| 7-140734621-T-A | RASopathy | Likely benign (Jun 28, 2023) | ||
| 7-140734621-TC-T | RASopathy | Uncertain significance (Jun 25, 2023) | ||
| 7-140734622-C-T | Cardiofaciocutaneous syndrome 1 | Likely pathogenic (May 28, 2019) | ||
| 7-140734627-T-A | RASopathy | Likely benign (Oct 03, 2022) | ||
| 7-140734633-G-C | RASopathy | Uncertain significance (Jun 01, 2021) | ||
| 7-140734633-GA-AC | Uncertain significance (Aug 19, 2016) | |||
| 7-140734635-T-C | RASopathy | Uncertain significance (Apr 25, 2022) | ||
| 7-140734645-T-C | RASopathy | Likely benign (Dec 22, 2021) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| BRAF | protein_coding | protein_coding | ENST00000288602 | 18 | 205438 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 1.00 | 0.0000476 | 125742 | 0 | 6 | 125748 | 0.0000239 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 3.72 | 203 | 417 | 0.487 | 0.0000215 | 4958 |
| Missense in Polyphen | 38 | 127.38 | 0.29833 | 1588 | ||
| Synonymous | -0.223 | 157 | 153 | 1.02 | 0.00000807 | 1528 |
| Loss of Function | 5.91 | 5 | 50.2 | 0.0996 | 0.00000324 | 511 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.0000289 | 0.0000289 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.00 | 0.00 |
| Finnish | 0.00 | 0.00 |
| European (Non-Finnish) | 0.0000352 | 0.0000352 |
| Middle Eastern | 0.00 | 0.00 |
| South Asian | 0.0000327 | 0.0000327 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus. May play a role in the postsynaptic responses of hippocampal neuron. Phosphorylates MAP2K1, and thereby contributes to the MAP kinase signal transduction pathway. {ECO:0000269|PubMed:21441910}.;
- Disease
- DISEASE: Note=Defects in BRAF are found in a wide range of cancers. {ECO:0000269|PubMed:18974108}.; DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. {ECO:0000269|PubMed:12198537, ECO:0000269|PubMed:21917714, ECO:0000269|PubMed:23263490, ECO:0000269|PubMed:24455489}. Note=The disease may be caused by mutations affecting the gene represented in this entry.; DISEASE: Lung cancer (LNCR) [MIM:211980]: A common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. {ECO:0000269|PubMed:12460919}. Note=The gene represented in this entry is involved in disease pathogenesis.; DISEASE: Familial non-Hodgkin lymphoma (NHL) [MIM:605027]: Cancer that starts in cells of the lymph system, which is part of the body's immune system. NHLs can occur at any age and are often marked by enlarged lymph nodes, fever and weight loss. {ECO:0000269|PubMed:14612909}. Note=The gene represented in this entry is involved in disease pathogenesis.; DISEASE: Cardiofaciocutaneous syndrome 1 (CFC1) [MIM:115150]: A multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. {ECO:0000269|PubMed:16439621, ECO:0000269|PubMed:16474404, ECO:0000269|PubMed:18042262, ECO:0000269|PubMed:19206169}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Noonan syndrome 7 (NS7) [MIM:613706]: 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:19206169}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: LEOPARD syndrome 3 (LPRD3) [MIM:613707]: A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness. {ECO:0000269|PubMed:19206169}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=A chromosomal aberration involving BRAF is found in pilocytic astrocytomas. A tandem duplication of 2 Mb at 7q34 leads to the expression of a KIAA1549-BRAF fusion protein with a constitutive kinase activity and inducing cell transformation. {ECO:0000269|PubMed:18974108}.;
- Pathway
- Non-small cell lung cancer - Homo sapiens (human);Chronic myeloid leukemia - Homo sapiens (human);Gastric cancer - Homo sapiens (human);Focal adhesion - Homo sapiens (human);mTOR signaling pathway - Homo sapiens (human);Renal cell carcinoma - Homo sapiens (human);Long-term potentiation - Homo sapiens (human);Neurotrophin signaling pathway - Homo sapiens (human);Serotonergic synapse - Homo sapiens (human);Melanoma - Homo sapiens (human);Cushing,s syndrome - Homo sapiens (human);Bladder cancer - Homo sapiens (human);Long-term depression - Homo sapiens (human);Acute myeloid leukemia - Homo sapiens (human);Breast cancer - Homo sapiens (human);ErbB signaling pathway - Homo sapiens (human);FoxO signaling pathway - Homo sapiens (human);Chemokine signaling pathway - Homo sapiens (human);Regulation of actin cytoskeleton - Homo sapiens (human);Hepatocellular carcinoma - Homo sapiens (human);Glioma - Homo sapiens (human);Prostate cancer - Homo sapiens (human);cAMP signaling pathway - Homo sapiens (human);Vascular smooth muscle contraction - Homo sapiens (human);Rap1 signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Natural killer cell mediated cytotoxicity - Homo sapiens (human);Proteoglycans in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Hepatitis C - Homo sapiens (human);Thyroid cancer - Homo sapiens (human);Pancreatic cancer - Homo sapiens (human);Endometrial cancer - Homo sapiens (human);Colorectal cancer - Homo sapiens (human);Alcoholism - Homo sapiens (human);Insulin signaling pathway - Homo sapiens (human);Progesterone-mediated oocyte maturation - Homo sapiens (human);Pathway_PA165959425;Sorafenib Pharmacodynamics;Vemurafenib Pathway, Pharmacodynamics;update your name in edit mode;Intracellular Signalling Through Adenosine Receptor A2b and Adenosine;Intracellular Signalling Through Adenosine Receptor A2a and Adenosine;EGF-Core;Integrin-mediated Cell Adhesion;Human Thyroid Stimulating Hormone (TSH) signaling pathway;Signaling Pathways in Glioblastoma;B Cell Receptor Signaling Pathway;Corticotropin-releasing hormone signaling pathway;Integrated Lung Cancer Pathway;Polycystic Kidney Disease Pathway;Bladder Cancer;Focal Adhesion;BDNF-TrkB Signaling;MAPK Signaling Pathway;Chemokine signaling pathway;ESC Pluripotency Pathways;Endometrial cancer;MET in type 1 papillary renal cell carcinoma;Chromosomal and microsatellite instability in colorectal cancer;MAPK Cascade;EGF-EGFR Signaling Pathway;Regulation of Actin Cytoskeleton;Senescence and Autophagy in Cancer;Estrogen signaling pathway;Serotonin HTR1 Group and FOS Pathway;Serotonin Receptor 4-6-7 and NR3C Signaling;Negative regulation of FGFR2 signaling;Signaling by FGFR2;MAP2K and MAPK activation;RAF activation;Disease;Negative regulation of FGFR3 signaling;Signaling by FGFR3;Signal Transduction;Negative regulation of FGFR4 signaling;Signaling by FGFR4;Signaling by FGFR;Spry regulation of FGF signaling;B cell receptor signaling;GPCR Adenosine A2A receptor;GPCR GroupI metabotropic glutamate receptor;GPCR signaling-G alpha q;CD4 T cell receptor signaling-ERK cascade;ARMS-mediated activation;IGF signaling;FGF;Negative feedback regulation of MAPK pathway;Neuronal System;GPCR signaling-G alpha s Epac and ERK;Signalling to p38 via RIT and RIN;IL-7 signaling;GPCR signaling-G alpha s PKA and ERK;Frs2-mediated activation;Prolonged ERK activation events;Signalling to ERKs;Signaling by NTRK1 (TRKA);Integrin;Signaling by NTRKs;EGFR1;Ras signaling in the CD4+ TCR pathway;ErbB1 downstream signaling;Negative regulation of MAPK pathway;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;JAK STAT pathway and regulation;NGF;EPO signaling;Neurotransmitter receptors and postsynaptic signal transmission;Transmission across Chemical Synapses;CREB phosphorylation through the activation of Ras;Post NMDA receptor activation events;Activation of NMDA receptor and postsynaptic events;Signaling by Receptor Tyrosine Kinases;Signaling by RAS mutants;VEGF;Signaling by high-kinase activity BRAF mutants;Signaling by moderate kinase activity BRAF mutants;Paradoxical activation of RAF signaling by kinase inactive BRAF;mTOR signaling pathway;Signaling by BRAF and RAF fusions;Oncogenic MAPK signaling;Diseases of signal transduction;CDC42 signaling events;Downstream signaling in naïve CD8+ T cells;Signaling events mediated by focal adhesion kinase;PDGFR-beta signaling pathway;Trk receptor signaling mediated by the MAPK pathway;Signaling events mediated by VEGFR1 and VEGFR2;Negative regulation of FGFR1 signaling;Signaling by FGFR1;CD4 T cell receptor signaling
(Consensus)
Intolerance Scores
- loftool
- 0.0212
- rvis_EVS
- -0.6
- rvis_percentile_EVS
- 17.75
Haploinsufficiency Scores
- pHI
- 0.954
- hipred
- Y
- hipred_score
- 0.843
- ghis
- 0.559
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- S
- essential_gene_gene_trap
- K
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.853
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Braf
- Phenotype
- liver/biliary system phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; pigmentation phenotype; neoplasm; 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); reproductive 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); vision/eye phenotype; digestive/alimentary phenotype; limbs/digits/tail 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); skeleton phenotype; renal/urinary system phenotype; immune system phenotype; homeostasis/metabolism phenotype; cellular phenotype; endocrine/exocrine gland phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); 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); craniofacial phenotype; muscle phenotype;
Gene ontology
- Biological process
- MAPK cascade;activation of MAPKK activity;myeloid progenitor cell differentiation;protein phosphorylation;visual learning;animal organ morphogenesis;positive regulation of gene expression;negative regulation of fibroblast migration;positive regulation of glucose transmembrane transport;thyroid gland development;positive regulation of peptidyl-serine phosphorylation;somatic stem cell population maintenance;cellular response to drug;regulation of cell population proliferation;negative regulation of apoptotic process;CD4-positive, alpha-beta T cell differentiation;CD4-positive or CD8-positive, alpha-beta T cell lineage commitment;response to peptide hormone;negative regulation of neuron apoptotic process;regulation of T cell differentiation;thymus development;positive regulation of axon regeneration;positive regulation of axonogenesis;T cell receptor signaling pathway;protein heterooligomerization;positive regulation of stress fiber assembly;response to cAMP;long-term synaptic potentiation;head morphogenesis;face development;positive regulation of ERK1 and ERK2 cascade;trehalose metabolism in response to stress;cellular response to calcium ion;establishment of protein localization to membrane;positive regulation of substrate adhesion-dependent cell spreading;cellular response to nerve growth factor stimulus;negative regulation of synaptic vesicle exocytosis;negative regulation of endothelial cell apoptotic process
- Cellular component
- nucleus;mitochondrion;cytosol;plasma membrane;neuron projection;intracellular membrane-bounded organelle;cell body
- Molecular function
- protein kinase activity;protein serine/threonine kinase activity;MAP kinase kinase kinase activity;calcium ion binding;protein binding;ATP binding;small GTPase binding;mitogen-activated protein kinase kinase binding;identical protein binding;protein heterodimerization activity