NEFL

neurofilament light chain, the group of Intermediate filaments Type IV|Protein phosphatase 1 regulatory subunits|MicroRNA protein coding host genes

Basic information

Region (hg38): 8:24950954-24956721

Links

ENSG00000277586 ∙ NCBI:4747 ∙ OMIM:162280 ∙ HGNC:7739 ∙ Uniprot:P07196 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Charcot-Marie-Tooth disease type 2E (Supportive), mode of inheritance: AD
• Charcot-Marie-Tooth disease type 1F (Supportive), mode of inheritance: AD
• Charcot-Marie-Tooth disease type 2B5 (Supportive), mode of inheritance: AR
• Charcot-Marie-Tooth disease type 1F (Strong), mode of inheritance: AR
• Charcot-Marie-Tooth disease type 1F (Strong), mode of inheritance: AD
• Charcot-Marie-Tooth disease type 2 (Definitive), mode of inheritance: AR
• Charcot-Marie-Tooth disease (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Charcot-Marie-Tooth disease, axonal, type 2E; Charcot-Marie-Tooth disease, dominant intermediate G; Charcot-Marie-Tooth disease, type 1F	AD/AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Neurologic	10841809; 12481988; 14733962; 15111691; 16619203; 17620486; 18758688; 19158810; 19286384; 20039262; 20301366; 22206013; 24887401; 25877835; 26645395; 28364294

ClinVar

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

• Charcot-Marie-Tooth disease type 2E (367 variants)
• not provided (128 variants)
• Inborn genetic diseases (77 variants)
• Charcot-Marie-Tooth disease (56 variants)
• Charcot-Marie-Tooth disease type 1F (52 variants)
• not specified (33 variants)
• Charcot-Marie-Tooth disease, type I (18 variants)
• Charcot-Marie-Tooth disease, dominant intermediate G (6 variants)
• Peripheral neuropathy (2 variants)
• Charcot-Marie-Tooth disease type 1F;Charcot-Marie-Tooth disease type 2E;Charcot-Marie-Tooth disease, dominant intermediate G (2 variants)
• Charcot-Marie-Tooth disease type 1C (1 variants)
• Auditory neuropathy (1 variants)
• Pes cavus;Peripheral neuropathy;Distal lower limb muscle weakness (1 variants)
• Sensorineural hearing loss disorder;Developmental disorder (1 variants)
• Charcot-Marie-Tooth disease, axonal, type 2EE (1 variants)
• Charcot-Marie-Tooth disease type 2E;Charcot-Marie-Tooth disease, dominant intermediate G;Charcot-Marie-Tooth disease type 1F (1 variants)
• Hereditary motor neuron disease (1 variants)
• Charcot-Marie-Tooth disease, dominant intermediate G;Charcot-Marie-Tooth disease type 2E;Charcot-Marie-Tooth disease type 1F (1 variants)
• Hand muscle atrophy;Peripheral demyelination;Distal muscle weakness;Decreased nerve conduction velocity;Peripheral neuropathy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NEFL 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			19	85	3	107
missense	8	8	250	5		271
nonsense	9	5	1			15
start loss						0
frameshift	7	2	2			11
inframe indel			15		1	16
splice donor/acceptor (+/-2bp)		1	1			2
splice region			5	1		6
non coding			17	25	12	54
Total	24	16	305	115	16

Highest pathogenic variant AF is 0.0000132

Variants in NEFL

This is a list of pathogenic ClinVar variants found in the NEFL region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
8-24951004-A-G		Charcot-Marie-Tooth disease type 1F	Benign (Jan 12, 2018)
8-24951066-A-G		Charcot-Marie-Tooth disease type 1F	Uncertain significance (Jan 12, 2018)
8-24951167-C-T		Charcot-Marie-Tooth disease, type I	Likely benign (Jun 14, 2016)
8-24951197-CTTCA-C		Charcot-Marie-Tooth disease, type I	Uncertain significance (Jun 14, 2016)
8-24951328-G-A		Charcot-Marie-Tooth disease type 1F	Uncertain significance (Jan 12, 2018)
8-24951346-T-C		Charcot-Marie-Tooth disease type 1F	Uncertain significance (Jan 12, 2018)
8-24951427-G-A		Charcot-Marie-Tooth disease type 1F	Uncertain significance (Jan 12, 2018)
8-24951461-A-C		Charcot-Marie-Tooth disease type 1F	Uncertain significance (Jan 12, 2018)
8-24951466-C-T		Charcot-Marie-Tooth disease type 1F	Benign (Jan 13, 2018)
8-24951467-GTTC-G		Charcot-Marie-Tooth disease, type I	Uncertain significance (Jun 14, 2016)
8-24951468-T-C		Charcot-Marie-Tooth disease type 1F	Uncertain significance (Jan 12, 2018)
8-24951517-T-C		Charcot-Marie-Tooth disease type 1F	Benign (Jan 13, 2018)
8-24951554-C-T		Charcot-Marie-Tooth disease, type I	Benign (Jun 14, 2016)
8-24951612-C-G		Charcot-Marie-Tooth disease, type I	Likely benign (Jun 14, 2016)
8-24951655-A-C		Charcot-Marie-Tooth disease, type I	Likely benign (Jun 14, 2016)
8-24951657-A-C		Charcot-Marie-Tooth disease type 1F	Uncertain significance (Jan 12, 2018)
8-24951703-G-A		Charcot-Marie-Tooth disease, type I	Likely benign (Jun 14, 2016)
8-24951709-C-T		Charcot-Marie-Tooth disease type 1F	Uncertain significance (Apr 27, 2017)
8-24951710-G-A		Charcot-Marie-Tooth disease, type I	Likely benign (Jun 14, 2016)
8-24951927-C-G		Charcot-Marie-Tooth disease, type I	Likely benign (Jun 14, 2016)
8-24951932-T-C		Charcot-Marie-Tooth disease type 1F	Benign (Jan 13, 2018)
8-24951954-A-G		Charcot-Marie-Tooth disease type 1F	Uncertain significance (Jan 13, 2018)
8-24952123-C-G		Charcot-Marie-Tooth disease, type I	Benign (Jun 14, 2016)
8-24952233-A-G		Charcot-Marie-Tooth disease type 1F	Uncertain significance (Jan 13, 2018)
8-24952244-GA-G		Charcot-Marie-Tooth disease, type I	Uncertain significance (Jun 14, 2016)

GnomAD

Source: gnomAD

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Neurofilaments usually contain three intermediate filament proteins: L, M, and H which are involved in the maintenance of neuronal caliber.
• Disease: DISEASE: Charcot-Marie-Tooth disease 1F (CMT1F) [MIM:607734]: A dominant demyelinating form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot- Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet. CMT1F is characterized by onset in infancy or childhood (range 1 to 13 years). {ECO:0000269|PubMed:12566280, ECO:0000269|PubMed:14733962, ECO:0000269|PubMed:15241803}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease 2E (CMT2E) [MIM:607684]: A dominant axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. {ECO:0000269|PubMed:10841809, ECO:0000269|PubMed:11220745, ECO:0000269|PubMed:12481988, ECO:0000269|PubMed:15241803, ECO:0000269|PubMed:22206013}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Amyotrophic lateral sclerosis (ALS) - Homo sapiens (human);Amyotrophic lateral sclerosis (ALS);Association Between Physico-Chemical Features and Toxicity Associated Pathways;NO-cGMP-PKG mediated Neuroprotection;Signal Transduction;Neuronal System;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;Neurotransmitter receptors and postsynaptic signal transmission;Transmission across Chemical Synapses;Ras activation upon Ca2+ influx through NMDA receptor;CREB phosphorylation through the activation of Ras;Unblocking of NMDA receptor, glutamate binding and activation;CREB phosphorylation through the activation of CaMKII;Post NMDA receptor activation events;Activation of NMDA receptor and postsynaptic events (Consensus)

Recessive Scores

• pRec: 0.658

Haploinsufficiency Scores

• pHI: 0.698

Essentials

• gene_indispensability_pred: E
• gene_indispensability_score: 0.871

Mouse Genome Informatics

• Gene name: Nefl
• 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); normal phenotype

Gene ontology

• Biological process: MAPK cascade;microtubule cytoskeleton organization;anterograde axonal transport;retrograde axonal transport;peripheral nervous system axon regeneration;axonal transport of mitochondrion;spinal cord development;hippocampus development;cerebral cortex development;regulation of axon diameter;neurofilament bundle assembly;locomotion;response to peptide hormone;negative regulation of neuron apoptotic process;intermediate filament polymerization or depolymerization;intermediate filament organization;neuron projection morphogenesis;positive regulation of axonogenesis;neuromuscular process controlling balance;protein polymerization;response to corticosterone;neurofilament cytoskeleton organization;synapse maturation;postsynaptic intermediate filament cytoskeleton organization;response to sodium arsenite;response to acrylamide
• Cellular component: cytoplasm;cytosol;neurofilament;axon;growth cone;neuromuscular junction;myelin sheath;Schaffer collateral - CA1 synapse;cholinergic synapse;postsynaptic intermediate filament cytoskeleton;presynaptic intermediate filament cytoskeleton;axon cytoplasm
• Molecular function: Ras guanyl-nucleotide exchange factor activity;structural constituent of cytoskeleton;protein binding;protein C-terminus binding;protein domain specific binding;protein binding, bridging;identical protein binding;phospholipase binding;protein heterodimerization activity;structural constituent of postsynaptic intermediate filament cytoskeleton