NF1

neurofibromin 1, the group of Armadillo like helical domain containing

Basic information

Region (hg38): 17:31094927-31382116

Links

ENSG00000196712 ∙ NCBI:4763 ∙ OMIM:613113 ∙ HGNC:7765 ∙ Uniprot:P21359 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• neurofibromatosis type 1 (Definitive), mode of inheritance: AD
• neurofibromatosis-Noonan syndrome (Definitive), mode of inheritance: AD
• neurofibromatosis type 1 (Definitive), mode of inheritance: AD
• Moyamoya disease (Moderate), mode of inheritance: AD
• neurofibromatosis-Noonan syndrome (Strong), mode of inheritance: AD
• neurofibromatosis type 1 (Strong), mode of inheritance: AD
• neurofibromatosis-Noonan syndrome (Supportive), mode of inheritance: AD
• hereditary pheochromocytoma-paraganglioma (Supportive), mode of inheritance: AD
• neurofibromatosis type 1 (Strong), mode of inheritance: AD
• familial ovarian cancer (No Known Disease Relationship), mode of inheritance: AD
• neurofibromatosis type 1 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Neurofibromatosis type 1; Neurofibromatosis-Noonan syndrome; Watson syndrome	AD	Cardiovascular; Oncologic; Ophthalmologic	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	Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal; Neurologic; Oncologic; Ophthalmologic	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; 32187457
The condition can involve multiple organ systems affected by neoplastic and other complications that would warrant intervention

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NF1 gene.

• Neurofibromatosis,_type_1 (12525 variants)
• Hereditary_cancer-predisposing_syndrome (7016 variants)
• Cardiovascular_phenotype (6358 variants)
• not_provided (2762 variants)
• Juvenile_myelomonocytic_leukemia (972 variants)
• not_specified (658 variants)
• Neurofibromatosis-Noonan_syndrome (623 variants)
• Caf�-au-lait_macules_with_pulmonary_stenosis (607 variants)
• Neurofibromatosis,_familial_spinal (606 variants)
• NF1-related_disorder (427 variants)
• Tibial_pseudarthrosis (46 variants)
• Cafe_au_lait_spots,_multiple (21 variants)
• Gastric_cancer (20 variants)
• Neurofibroma (18 variants)
• Hereditary_breast_ovarian_cancer_syndrome (15 variants)
• See_cases (12 variants)
• Inborn_genetic_diseases (11 variants)
• Malignant_tumor_of_urinary_bladder (11 variants)
• Abnormality_of_the_skin (10 variants)
• Rhabdomyosarcoma (9 variants)
• Axillary_freckling (8 variants)
• Cafe-au-lait_spot (8 variants)
• Hereditary_cancer (5 variants)
• Ovarian_cancer (5 variants)
• Chromosome_17q11.2_deletion_syndrome,_1.4Mb (5 variants)
• Optic_nerve_glioma (5 variants)
• Atypical_coarctation_of_aorta (5 variants)
• RASopathy (4 variants)
• Intellectual_disability (4 variants)
• EVI2A-related_disorder (3 variants)
• Neurofibromatosis (3 variants)
• OMG-related_disorder (3 variants)
• Neurofibromatosis_type_1_due_to_NF1_mutation_or_intragenic_deletion (3 variants)
• Inguinal_freckling (3 variants)
• Subcutaneous_neurofibroma (3 variants)
• Macrothrombocytopenia_and_granulocyte_inclusions_with_or_without_nephritis_or_sensorineural_hearing_loss (2 variants)
• Astrocytoma_IDH-mutant (2 variants)
• Lisch_nodules (2 variants)
• Ewing_sarcoma (2 variants)
• Abnormality_of_vision (2 variants)
• Pheochromocytoma (1 variants)
• Motor_delay (1 variants)
• EEG_with_generalized_slow_activity (1 variants)
• Autism_spectrum_disorder (1 variants)
• Microcephaly (1 variants)
• Delayed_speech_and_language_development (1 variants)
• Focal_T2_hyperintense_basal_ganglia_lesion (1 variants)
• Hereditary_pheochromocytoma-paraganglioma (1 variants)
• Lymphedema (1 variants)
• Keratoconus (1 variants)
• Large_cafe-au-lait_macules_with_irregular_margins (1 variants)
• Craniopharyngioma (1 variants)
• Diffuse_midline_glioma,_H3_K27-altered (1 variants)
• Acute_monoblastic_leukemia (1 variants)
• Tuberous_sclerosis_syndrome (1 variants)
• Developmental_defect_during_embryogenesis (1 variants)
• Strabismus (1 variants)
• Neurodevelopmental_delay (1 variants)
• Diffuse_intrinsic_pontine_glioma (1 variants)
• Abnormal_lymph_node_morphology (1 variants)
• Neurofibrmatosis_type_1 (1 variants)
• Visual_loss (1 variants)
• Acute_monocytic_leukemia (1 variants)
• Vascular_dilatation (1 variants)
• Spinal_neurofibroma (1 variants)
• Retinoblastoma (1 variants)
• Macrocephaly (1 variants)
• Floppy_infant (1 variants)
• Hyperactivity (1 variants)
• Neoplasm_of_brain (1 variants)
• Abnormality_of_macular_pigmentation (1 variants)
• Delayed_fine_motor_development (1 variants)
• Myopathy,_centronuclear,_5 (1 variants)
• Multiple_myeloma (1 variants)
• Febrile_seizure_(within_the_age_range_of_3_months_to_6_years) (1 variants)
• Moyamoya_angiopathy (1 variants)
• Increased_nuchal_translucency (1 variants)
• Thoracic_scoliosis (1 variants)
• Precursor_B-cell_acute_lymphoblastic_leukemia (1 variants)
• Neurocutaneous_syndrome (1 variants)
• Bardet-Biedl_syndrome_9 (1 variants)
• Male_infertility_with_azoospermia_or_oligozoospermia_due_to_single_gene_mutation (1 variants)
• Abnormal_electroretinogram (1 variants)
• Premature_birth (1 variants)
• Myeloproliferative_neoplasm,_unclassifiable (1 variants)
• Focal-onset_seizure (1 variants)
• Cleft_palate (1 variants)
• Diffuse_pediatric-type_high-grade_glioma,_H3-wildtype_and_IDH-wildtype (1 variants)
• Malignant_lymphoma,_large_B-cell,_diffuse (1 variants)
• Cervical_lymphadenopathy (1 variants)
• Plexiform_neurofibroma (1 variants)
• Pilocytic_astrocytoma (1 variants)
• Abnormal_macular_morphology (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NF1 gene is commonly pathogenic or not. These statistics are base on transcript: NM_001042492.3. 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	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous	20	19	56	2450	10	2555
missense	166	523	5271	356	9	6325
nonsense	824	76	6			906
start loss	6	4				10
frameshift	2589	343	23	1		2956
splice donor/acceptor (+/-2bp)	397	285	20	10	3	715
Total	4002	1250	5376	2817	22

Highest pathogenic variant AF is 0.0012209151

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NF1	protein_coding	protein_coding	ENST00000358273	58	287190

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.902	0.0983	125696	0	52	125748	0.000207

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	6.54	771	1.48e+3	0.521	0.0000783	18724
Missense in Polyphen		312	753.78	0.41392		9838
Synonymous	1.12	497	530	0.938	0.0000276	5406
Loss of Function	8.73	31	144	0.215	0.00000775	1748

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000384	0.000384
Ashkenazi Jewish	0.000307	0.000298
East Asian	0.000163	0.000163
Finnish	0.000140	0.000139
European (Non-Finnish)	0.000238	0.000237
Middle Eastern	0.000163	0.000163
South Asian	0.000134	0.000131
Other	0.000163	0.000163

dbNSFP

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.
• Pathway: Ras signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Pilocytic astrocytoma;Signaling Pathways in Glioblastoma;Aryl Hydrocarbon Receptor;MECP2 and Associated Rett Syndrome;MAPK Signaling Pathway;Ras Signaling;Regulation of Ras family activation;Signal Transduction;Regulation of RAS by GAPs;ATF-2 transcription factor network;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;chromatin remodeling by hswi/snf atp-dependent complexes;FOXA2 and FOXA3 transcription factor networks;Syndecan-2-mediated signaling events (Consensus)

Recessive Scores

• pRec: 0.908

Intolerance Scores

• loftool: 0.116
• rvis_EVS: -3.09
• rvis_percentile_EVS: 0.47

Haploinsufficiency Scores

• pHI: 0.600
• hipred: Y
• hipred_score: 0.695
• ghis: 0.636

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.894

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Nf1
• 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; muscle phenotype; craniofacial phenotype; homeostasis/metabolism phenotype; cellular phenotype; skeleton phenotype; renal/urinary system phenotype; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; respiratory 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); 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); pigmentation phenotype; neoplasm; digestive/alimentary phenotype; limbs/digits/tail 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); vision/eye phenotype; immune system phenotype

Zebrafish Information Network

• Gene name: nf1b
• Affected structure: atrioventricular valve
• Phenotype tag: abnormal
• Phenotype quality: decreased functionality

Gene ontology

• Biological process: MAPK cascade;osteoblast differentiation;metanephros development;response to hypoxia;liver development;negative regulation of endothelial cell proliferation;positive regulation of endothelial cell proliferation;regulation of cell-matrix adhesion;negative regulation of cell-matrix adhesion;negative regulation of protein kinase activity;cell communication;Ras protein signal transduction;negative regulation of neuroblast proliferation;brain development;peripheral nervous system development;heart development;skeletal muscle tissue development;visual learning;extrinsic apoptotic signaling pathway via death domain receptors;regulation of gene expression;Schwann cell development;phosphatidylinositol 3-kinase signaling;negative regulation of angiogenesis;spinal cord development;amygdala development;forebrain astrocyte development;neural tube development;cerebral cortex development;myelination in peripheral nervous system;actin cytoskeleton organization;extracellular matrix organization;collagen fibril organization;adrenal gland development;negative regulation of cell migration;regulation of synaptic transmission, GABAergic;cellular response to heat;negative regulation of Rac protein signal transduction;wound healing;negative regulation of protein import into nucleus;positive regulation of apoptotic process;regulation of GTPase activity;negative regulation of MAP kinase activity;negative regulation of MAPK cascade;pigmentation;positive regulation of neuron apoptotic process;regulation of blood vessel endothelial cell migration;positive regulation of GTPase activity;regulation of bone resorption;negative regulation of osteoclast differentiation;regulation of glial cell differentiation;positive regulation of adenylate cyclase activity;regulation of angiogenesis;negative regulation of neurotransmitter secretion;negative regulation of fibroblast proliferation;regulation of long-term neuronal synaptic plasticity;sympathetic nervous system development;camera-type eye morphogenesis;negative regulation of astrocyte differentiation;negative regulation of oligodendrocyte differentiation;smooth muscle tissue development;hair follicle maturation;artery morphogenesis;forebrain morphogenesis;cognition;gamma-aminobutyric acid secretion, neurotransmission;glutamate secretion, neurotransmission;observational learning;regulation of long-term synaptic potentiation;positive regulation of extrinsic apoptotic signaling pathway via death domain receptors;positive regulation of extrinsic apoptotic signaling pathway in absence of ligand
• Cellular component: nucleus;nucleolus;cytoplasm;cytosol;membrane;axon;dendrite;presynapse
• Molecular function: GTPase activator activity;protein binding;phosphatidylethanolamine binding;phosphatidylcholine binding