RAF1
protein-codingRaf-1 proto-oncogene, serine/threonine kinase, the group of Mitogen-activated protein kinase kinase kinases|RAF family
Gene summary
This gene is the cellular homolog of viral raf gene (v-raf). The encoded protein is a MAP kinase kinase kinase (MAP3K), which functions downstream of the Ras family of membrane associated GTPases to which it binds directly. Once activated, the cellular RAF1 protein can phosphorylate to activate the dual specificity protein kinases MEK1 and MEK2, which in turn phosphorylate to activate the serine/threonine specific protein kinases, ERK1 and ERK2. Activated ERKs are pleiotropic effectors of cell physiology and play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration. Mutations in this gene are associated with Noonan syndrome 5 and LEOPARD syndrome 2. [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 ~82.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014396
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0018997
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0012690
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0012691
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0012690
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007893
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0015470
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014396
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0012690
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0012690
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014396
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0015280
Submitter: ClinGen
There has only been one case identified with suspected cardiofaciocutaneous syndrome (CFC) and a RAF1 variant (Hakami, Dillon, Lebo, & Mason-Suares, 2016). The patient was a newborn and the CFC diagnosis was based on prenatal findings of cystic hygroma, congenital heart defect and increased nuchal translucency combined with newborn phenotyping. The study admits that the diagnosis for a specific Noonan spectrum disorder may be inaccurate, as facial anomalies change with time. The p.S257L variant has also been identified in cases with RAF1-Noonan syndrome (NS). Therefore, this association is classified as Disputed. Of note, RAF1 is also classified as Definitive in association with Noonan syndrome (NS), Limited in association with NS with multiple lentigines, and as Disputed in association with Costello syndrome. The ClinGen RASopathy Expert Panel found no evidence associating RAF1 with NS-like disorder with loose anagen hair. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 5/31/18 (SOP Version 5).
Inheritance Pattern: AD
Disease ID:MONDO:0012691
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0012690
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007893
Submitter: ClinGen
There was only sufficient evidence in the literature for the association between RAF1 and Noonan syndrome with multiple lentigines (NSML) association to be classified as Limited. Only two variants with supporting evidence for pathogenicity (one de novo) in this gene have been found in individuals with NSML (Carcavilla et al., 2013; Kuburovic, Vukomanovic, Carcavilla, Ezquieta-Zubicaray, & Kuburovic, 2011; Pandit et al., 2007). The RAF1 gene is also located in the Ras/MAPK pathway, which is associated with the NSML phenotype (Aoki et al., 2016; Rauen, 2013). Of note, RAF1 is also classified as Definitive in association with Noonan syndrome (NS) and as Disputed in association with Costello syndrome and cardiofaciocutaneous syndrome. The ClinGen RASopathy Expert Panel found no evidence associating RAF1 with NS-like disorder with loose anagen hair. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 7/25/18 (SOP Version 5).
Inheritance Pattern: AD
Disease ID:MONDO:0018997
Submitter: ClinGen
*RAF1* was first reported in relation to autosomal dominant Noonan syndrome in 2007 (Pandit et al., PMID: 17603483; Razzaque et al., PMID:17603482). The *RAF1* gene is located in the Ras/MAPK pathway, which is associated with the NS phenotype and variants in this gene found in patients disrupt the RAS pathway function. Of note, *RAF1* is also classified as Limited in association with NS with multiple lentigines and as Disputed in association with Costello syndrome and cardiofaciocutaneous syndrome. The GCEP found no evidence associating *RAF1* with NS-like disorder with loose anagen hair. The typical prenatal Noonan presentation includes increased nuchal translucency/nuchal fold, which is seen in the first trimester and may persist throughout later stages of the prenatal course, as well as other lymphatic anomalies (pleural and pericardial effusion, ascites, fetal hydrops). Hypertrophic cardiomyopathy, hydronephrosis, short long bones, and various brain abnormalities may be observed. Other prenatal manifestations may include (progressive) polyhydramnios, absence of the ductus venosis and possible intrauterine fetal demise (PMIDs: 22821648, 26467173, 28777121, 30359267, 29907801, 36155125, 35278234). Nine unique variants (missense and deletion) that have been reported in 21 probands in 13 publications (PMIDs: 17603483, 17603482, 25706034, 23877478, 23613113, 22821648, 20052757, 26467173, 28777121, 29907801, 30359267, 36155125, 35278234) are included in this curation. The maximum amount of scores for genetic evidence has been reached. This gene-disease relationship is supported by a protein interaction study showing *RAF1* as an established gene in the RAS/MAPK pathway and a mouse model replicating the human disease (PMIDs: 23613113, 21339642). In summary, there is definitive evidence to support the relationship between *RAF1* and autosomal dominant Noonan syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Rasopathies GCEP on 7/24/18 as per SOP v5. It was reevaluated in 2024 using SOP v10 to include prenatal Noonan cases. As a result of this reevaluation, this record underwent an update in scoring to be consistent with SOP v10. New case level evidence has been added, and the classification remained the same (PMIDs: 26467173, 28777121, 30359267, 29907801, 36155125, 35278234). This classification was approved by the ClinGen RASopathies GCEP on the meeting date October 23rd, 2024 (SOP Version 10).
Inheritance Pattern: AD
Disease ID:MONDO:0012691
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0009026
Submitter: ClinGen
Only 2 cases with RAF1 variants and a suspected Costello syndrome (CS) diagnosis have been published in the literature (Kobayashi et al., 2010). The authors state that they did not receive detailed clinical manifestations for one patient with a p.P261L variant of unknown origin and significance. The other case had a de novo p.N262K variant, but the patient died at 1 month of age and was not phenotyped directly by the authors. Both variants, p.P261L and p.N262K, were functionally assessed; however, due to lack of clinical manifestations obtained for these patients, this association is classified as Disputed. The HRAS gene is believed to be the only gene associated with CS (Aoki et al., 2005; Estep, Tidyman, Teitell, Cotter, & Rauen, 2006; Gripp et al., 2006; Kerr et al., 2006; Zampino et al., 2007). Of note, RAF1 is also classified as Definitive in association with Noonan syndrome (NS), Limited in association with NS with multiple lentigines, and as Disputed in association with cardiofaciocutaneous syndrome. The ClinGen RASopathy Expert Panel found no evidence associating RAF1 with NS-like disorder with loose anagen hair. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 7/24/18 (SOP Version 5).
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Dermatologic; Genitourinary; Hematologic; Musculoskeletal; Neurologic
Intervention: Cardiovascular; Hematologic
Rationale: In Dilated cardiomyopathy, individuals may present in pediatric without other syndromic findings, and awareness may allow early surveillance and management; In LEOPARD and Noonan syndromes, surveillance and treatment related to manifestations such as cardiac anomalies (which include hypertrophic cardiomyopathy) and short stature can be beneficial; Precautions regarding bleeding risk can be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to RAF1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002880.4. 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 | 8 | 261 | 8 | 277 | ||
| missense | 12 | 52 | 523 | 40 | 6 | 633 |
| nonsense | 12 | 2 | 14 | |||
| start loss | 1 | 1 | ||||
| frameshift | 18 | 1 | 19 | |||
| splice donor/acceptor (+/-2bp) | 8 | 2 | 10 | |||
| Total | 12 | 52 | 570 | 306 | 14 | 954 |
Highest pathogenic variant AF is 0.000008054193
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002871.1 | 16 | MANE Select | |
| Ensembl | ENSP00000251849.4 | 16 | MANE Select | |
| RefSeq | NP_001341618.1 | 17 | Standard | |
| RefSeq | NP_001341619.1 | 16 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| raf1a | Danio rerio | Structure: otolith Quality: position abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- 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)
- Focal adhesion - Homo sapiens (human)
Biological Process
- MAPK cascade
- activation of MAPKK activity
- response to hypoxia
- stimulatory C-type lectin receptor signaling pathway
- protein phosphorylation
Molecular Function
- protein kinase activity
- protein serine/threonine kinase activity
- MAP kinase kinase kinase activity
- protein binding
- ATP binding
Cellular Component
- cytoplasm
- mitochondrion
- mitochondrial outer membrane
- Golgi apparatus
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000251849
- Coding exons
- 16
- Length
- 80626
- Individuals with no LoFs
- 125737
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 11
- Defined
- 125748
- p
- 0.0000437
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.46 | 234 | 367 | 0.638 | 0.0000214 | 4279 |
| Missense (PolyPhen) | 42 | 118.72 | 0.35376 | 1370 | ||
| Synonymous | 0.0629 | 134 | 135 | 0.993 | 0.00000783 | 1249 |
| Loss of Function | 4.58 | 7 | 37.1 | 0.189 | 0.00000218 | 400 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.000053 | 0.000053 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including proliferation, differentiation, apoptosis, survival and oncogenic transformation. RAF1 activation initiates a mitogen-activated protein kinase (MAPK) cascade that comprises a sequential phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and MAP2K2/MEK2) and the extracellular signal-regulated kinases (MAPK3/ERK1 and MAPK1/ERK2). The phosphorylated form of RAF1 (on residues Ser-338 and Ser-339, by PAK1) phosphorylates BAD/Bcl2- antagonist of cell death at 'Ser-75'. Phosphorylates adenylyl cyclases: ADCY2, ADCY5 and ADCY6, resulting in their activation. Phosphorylates PPP1R12A resulting in inhibition of the phosphatase activity. Phosphorylates TNNT2/cardiac muscle troponin T. Can promote NF-kB activation and inhibit signal transducers involved in motility (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2), proliferation and angiogenesis (RB1). Can protect cells from apoptosis also by translocating to the mitochondria where it binds BCL2 and displaces BAD/Bcl2-antagonist of cell death. Regulates Rho signaling and migration, and is required for normal wound healing. Plays a role in the oncogenic transformation of epithelial cells via repression of the TJ protein, occludin (OCLN) by inducing the up-regulation of a transcriptional repressor SNAI2/SLUG, which induces down-regulation of OCLN. Restricts caspase activation in response to selected stimuli, notably Fas stimulation, pathogen-mediated macrophage apoptosis, and erythroid differentiation. {ECO:0000269|PubMed:11427728, ECO:0000269|PubMed:11719507, ECO:0000269|PubMed:15385642, ECO:0000269|PubMed:15618521, ECO:0000269|PubMed:15849194, ECO:0000269|PubMed:16892053, ECO:0000269|PubMed:16924233, ECO:0000269|PubMed:9360956}.;
- Disease
- DISEASE: Noonan syndrome 5 (NS5) [MIM:611553]: 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:17603482, ECO:0000269|PubMed:17603483, ECO:0000269|PubMed:20683980}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: LEOPARD syndrome 2 (LPRD2) [MIM:611554]: A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness. {ECO:0000269|PubMed:17603483}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, dilated 1NN (CMD1NN) [MIM:615916]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:24777450}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.931
Intolerance Scores
- LoFtool
- 0.184
- RVIS EVS
- -0.65
- RVIS percentile EVS
- 16.44
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- K
- Indispensability pred.
- E
- Indispensability score
- 0.999
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |