GeneBe

NF1

protein-coding

neurofibromin 1, the group of Armadillo like helical domain containing

Gene summary

This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001042492.3

Inheritance

AD

ClinVar variants

P:5616U:5496B:3326

Top phenotype

Neurofibromatosis type 1; Neurofibromatosis-Noonan syndrome; Watson syndrome

gnomAD constraint

pLI —, LoF o/e 0.22

Max pathogenic AF

—

Genomic locus

chr17:31,094,927-31,382,116

External References & Databases

Ensembl (ENSG00000196712)NCBI Gene (4763)OMIM (613113)HGNC:7765GenCCUniProt (P21359)AlphaFoldClinVar (NF1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~287.2 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial ovarian cancerNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0016248

Submitter: ClinGen

neurofibromatosis type 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0018975

Submitter: PanelApp Australia

Moyamoya diseaseMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0016820

Submitter: Genomics England PanelApp

neurofibromatosis type 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018975

Submitter: G2P

hereditary pheochromocytoma-paragangliomaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017366

Submitter: Orphanet

neurofibromatosis type 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0018975

Submitter: Genomics England PanelApp

neurofibromatosis-Noonan syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011035

Submitter: Genomics England PanelApp

neurofibromatosis type 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018975

Submitter: ClinGen

The relationship between NF1 and Neurofibromatosis Type 1 (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework as of February 26th, 2019. Variants in NF1 were first reported in humans with this disease as early as 1990 (Wallace et al., PMID 2134734). Diagnosis of Neurofibromatous Type 1 is based on criteria established by the NIH (1988; PMID 3152465). At least 3000 unique germline variants have been identified (reviewed in Gutmann et al., 2017; PMID 28230061). This gene-disease relationship is well-known and therefore a significant amount of case-level data, segregation data and experimental data is available in the literature, therefore the maximum score for both genetic evidence and experimental evidence has been reached. Note, this curation effort may not be exhaustive of all literature related to this gene-disease relationship. In particular, earlier compelling evidence suggestive of the gene-disease relationship, such as linkage data, may not be reflected in the current curation. The mechanism for disease is likely loss of function as NF1 encodes neurofibromin, which regulates cell growth and survival through downstream signaling pathways and loss of nuerofibromin is predicted to lead to increased cell growth (reviewed in Gutmann et al., 2017; PMID 28230061). Of note, this gene has also been implicated in familial spinal Neurofibromatosis, Neurofibromatosis-Noonan syndrome, Watson syndrome and juvenile myelomonocytic leukemia (AD). NF1 patients with features more consistent with Noonan syndrome in addition to Neurofibromatosis Type 1 have been described as having Neurofibromatosis-Noonan syndrome (Baralle et al., 2003; PMID 12707950, De Luca et al., 2005; PMID 16380919, Stevenson et al., 2006; PMID 16542390, Chen et al., 2014; PMID 25049390). However, after further review of the phenotypes described in these patients, the ClinGen RASopathy Expert Panel has decided that these presentations are consistent with what would be expected in patients with NF1 Neurofibromatosis Type 1. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability for the disease entities mentioned and therefore they have been lumped into one disease entity, Neurofibromatosis Type 1. In summary, NF1 is definitively associated with autosomal dominant Neurofibromatosis Type 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen General Gene Curation Expert Panel on February 27, 2019.

neurofibromatosis-Noonan syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011035

Submitter: Orphanet

neurofibromatosis type 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0018975

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Neurofibromatosis type 1; Neurofibromatosis-Noonan syndrome; Watson syndromeAD

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal; Neurologic; Oncologic; Ophthalmologic

Intervention: Cardiovascular; Oncologic; Ophthalmologic

Rationale: As clinical diagnosis can be challenging early, and optic pathway gliomas affect approximately 15% of people with NF1 (a minority can cause blindness), children should undergo surveillance by a pediatric ophthalmologist to screen for evidence of optic nerve damage from an occult optic nerve glioma; Surveillance for other manifestations and their sequelae, such as cardiovacular anomalies, may also be beneficial; Awareness of the risk of malignancy (in addition to benign neurofibromas and optic gliomas, NF1 includes a risk of brain tumors, and malignant peripheral nerve sheath tumors, as well as hematologic malignancies) may allow prompt detection and management; An antineoplastic agent (selumetinib) has been reported to improve some clinical parameters, such as pain, quality of life, strength, and range of motion

Comments: The condition can involve multiple organ systems affected by neoplastic and other complications that would warrant intervention

Refs: 6798841; 14050005; 6025371; 4965691; 4633999; 1131001; 6777096; 6786260; 6814376; 6417335; 6422759; 3083645; 3083258; 2897130; 2510517; 2134734; 1770531; 1909491; 1719426; 1302608; 8317503; 7931405; 7874161; 7477989; 7502979; 8644707; 9128932; 9126041; 9529361; 10204844; 10480204; 10699117; 10951462; 11078559; 11041400; 11292406; 11298367; 11704931; 11453810; 11176707; 11296017; 11283797; 12011145; 12180143; 12089128; 12707950; 12588224; 12566521; 15019338; 16380919; 15690406; 16787982; 17105749; 17362838; 17327286; 17932395; 19845691; 19449407; 19117870; 20301288; 22934576; 22943186; 22961690; 22965642; 22965773; 23047517; 23047742; 23060584; 23071069; 23099008; 23696535 23812910; 32187457Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NF1 variants in ClinVar

103 Conditions Cataloged
Neurofibromatosis, type 1Total: 13510
Hereditary cancer-predisposing syndromeTotal: 7840
Cardiovascular phenotypeTotal: 7193
not providedTotal: 3234
Juvenile myelomonocytic leukemiaTotal: 1014
NF1-related disorderTotal: 985
not specifiedTotal: 978
Neurofibromatosis-Noonan syndromeTotal: 673

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001042492.3. 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.

EffectPLPVUSLBBSum
synonymous
3
clinvar
17
clinvar
58
clinvar
2589
clinvar
33
clinvar
 2700
missense
120
clinvar
558
clinvar
5355
clinvar
688
clinvar
13
clinvar
 6734
nonsense
750
clinvar
94
clinvar
8
clinvar
 852
start loss
6
clinvar
4
clinvar
 10
frameshift
2859
clinvar
484
clinvar
25
clinvar
 3368
splice donor/acceptor (+/-2bp)
388
clinvar
333
clinvar
50
clinvar
2
clinvar
1
clinvar
 774
Total41261490549632794714438

Highest pathogenic variant AF is 0.0012209151

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001042492.3RefSeqNP_001035957.158MANE Select
ENST00000358273.9EnsemblENSP00000351015.458MANE Select
NM_000267.4RefSeqNP_000258.157Standard
NM_001128147.3RefSeqNP_001121619.115Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
nf1bDanio rerio

Structure: atrioventricular valve

Quality: decreased functionality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Ras signaling pathway - Homo sapiens (human)
  • MAPK signaling pathway - Homo sapiens (human)
  • Pilocytic astrocytoma
  • Signaling Pathways in Glioblastoma
  • Aryl Hydrocarbon Receptor

Biological Process

  • MAPK cascade
  • osteoblast differentiation
  • metanephros development
  • response to hypoxia
  • liver development

Molecular Function

  • GTPase activator activity
  • protein binding
  • phosphatidylethanolamine binding
  • phosphatidylcholine binding

Cellular Component

  • nucleus
  • nucleolus
  • cytoplasm
  • cytosol
  • membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000358273
Coding exons
58
Length
287190
Individuals with no LoFs
125696
Homozygous LoFs
0
Heterozygous LoFs
52
Defined
125748
p
0.000207
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense6.547711.48e+30.5210.000078318724
Missense (PolyPhen)312753.780.413929838
Synonymous1.124975300.9380.00002765406
Loss of Function8.73311440.2150.000007751748

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000120.00012rare
Latino/Admixed American0.000260.00026rare
Ashkenazi Jewish0.000310.00030rare
East Asian0.000160.00016rare
Finnish0.000140.00014rare
European (Non-Finnish)0.000240.00024rare
South Asian0.000130.00013rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Stimulates the GTPase activity of Ras. NF1 shows greater affinity for Ras GAP, but lower specific activity. May be a regulator of Ras activity. {ECO:0000269|PubMed:2121371, ECO:0000269|PubMed:8417346}.;
Disease
DISEASE: Neurofibromatosis 1 (NF1) [MIM:162200]: A disease characterized by patches of skin pigmentation (cafe-au-lait spots), Lisch nodules of the iris, tumors in the peripheral nervous system and fibromatous skin tumors. Individuals with the disorder have increased susceptibility to the development of benign and malignant tumors. {ECO:0000269|PubMed:10220149, ECO:0000269|PubMed:10336779, ECO:0000269|PubMed:10607834, ECO:0000269|PubMed:10712197, ECO:0000269|PubMed:10980545, ECO:0000269|PubMed:11258625, ECO:0000269|PubMed:11735023, ECO:0000269|PubMed:11857752, ECO:0000269|PubMed:12522551, ECO:0000269|PubMed:12552569, ECO:0000269|PubMed:12746402, ECO:0000269|PubMed:1302608, ECO:0000269|PubMed:15060124, ECO:0000269|PubMed:15146469, ECO:0000269|PubMed:15520408, ECO:0000269|PubMed:15523642, ECO:0000269|PubMed:15948193, ECO:0000269|PubMed:17160901, ECO:0000269|PubMed:21089070, ECO:0000269|PubMed:2114220, ECO:0000269|PubMed:21838856, ECO:0000269|PubMed:23758643, ECO:0000269|PubMed:24413922, ECO:0000269|PubMed:7981679, ECO:0000269|PubMed:8081387, ECO:0000269|PubMed:8544190, ECO:0000269|PubMed:8807336, ECO:0000269|PubMed:8834249, ECO:0000269|PubMed:9003501, ECO:0000269|PubMed:9101300, ECO:0000269|PubMed:9150739, ECO:0000269|PubMed:9298829, ECO:0000269|PubMed:9668168}. Note=The disease is caused by mutations affecting the gene represented in this entry.; 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. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Watson syndrome (WTSN) [MIM:193520]: A syndrome characterized by the presence of pulmonary stenosis, cafe-au-lait spots, and mental retardation. It is considered as an atypical form of neurofibromatosis. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Familial spinal neurofibromatosis (FSNF) [MIM:162210]: Considered to be an alternative form of neurofibromatosis, showing multiple spinal tumors. {ECO:0000269|PubMed:11704931}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Neurofibromatosis-Noonan syndrome (NFNS) [MIM:601321]: Characterized by manifestations of both NF1 and Noonan syndrome (NS). NS is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. {ECO:0000269|PubMed:12707950, ECO:0000269|PubMed:16380919, ECO:0000269|PubMed:19845691}. Note=The disease is caused by mutations affecting the gene represented in this entry.; 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. Note=The gene represented in this entry may be involved in disease pathogenesis.;

Recessive Scores

pRec
0.908

Intolerance Scores

LoFtool
0.116
RVIS EVS
-3.09
RVIS percentile EVS
0.47

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.894

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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