NEFH

neurofilament heavy chain, the group of Intermediate filaments Type IV

Basic information

Region (hg38): 22:29480218-29491390

Links

ENSG00000100285

∙ NCBI:4744 ∙ OMIM:162230 ∙ HGNC:7737 ∙ Uniprot:P12036 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

Charcot-Marie-Tooth disease axonal type 2CC (Strong), mode of inheritance: AD
amyotrophic lateral sclerosis (Limited), mode of inheritance: AD
Charcot-Marie-Tooth disease axonal type 2CC (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 2CC	AD	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	27040688

ClinVar

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

not_provided (897 variants)
Inborn_genetic_diseases (222 variants)
NEFH-related_disorder (106 variants)
not_specified (26 variants)
Charcot-Marie-Tooth_disease_axonal_type_2CC (23 variants)
Amyotrophic_lateral_sclerosis_type_1 (7 variants)
Peripheral_neuropathy (2 variants)
Amyotrophic_lateral_sclerosis (2 variants)
Amyotrophic_lateral_sclerosis,_susceptibility_to (1 variants)
Charcot-Marie-Tooth_disease_axonal_type_2C (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NEFH gene is commonly pathogenic or not. These statistics are base on transcript: NM_000021076.4. 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	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	261 clinvar	15 clinvar	277
missense			512 clinvar	64 clinvar	7 clinvar	583
nonsense		1 clinvar	15 clinvar	3 clinvar	1 clinvar	20
start loss			2			2
frameshift	4 clinvar	3 clinvar	31 clinvar	3 clinvar	1 clinvar	42
splice donor/acceptor (+/-2bp)		1 clinvar	1 clinvar			2
Total	4	5	562	331	24

Highest pathogenic variant AF is 0.00000501705

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NEFH	protein_coding	protein_coding	ENST00000310624	4	11161

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.67e-12	0.435	125695	0	53	125748	0.000211

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.523	470	503	0.934	0.0000263	6534
Missense in Polyphen		32	25.777	1.2414		350
Synonymous	-0.520	223	213	1.05	0.0000120	2008
Loss of Function	1.28	22	29.5	0.745	0.00000145	469

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000757	0.000756
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000330	0.000326
Finnish	0.000280	0.000277
European (Non-Finnish)	0.000169	0.000167
Middle Eastern	0.000330	0.000326
South Asian	0.000131	0.000131
Other	0.000163	0.000163

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. NF-H has an important function in mature axons that is not subserved by the two smaller NF proteins.;
Disease: DISEASE: Amyotrophic lateral sclerosis (ALS) [MIM:105400]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5- 10% of the cases. {ECO:0000269|PubMed:7849698}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease 2CC (CMT2CC) [MIM:616924]: An 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:27040688}. 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 (Consensus)

Recessive Scores

pRec: 0.212

Intolerance Scores

loftool: 0.0978
rvis_EVS: 0.25
rvis_percentile_EVS: 69.57

Haploinsufficiency Scores

pHI: 0.181
hipred: N
hipred_score: 0.328
ghis: 0.405

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: N
essential_gene_gene_trap: N
gene_indispensability_pred: E
gene_indispensability_score: 0.611

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Nefh
Phenotype: cellular 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);

Gene ontology

Biological process: microtubule cytoskeleton organization;axonogenesis;cell projection assembly;neurofilament bundle assembly;peripheral nervous system neuron axonogenesis;neurofilament cytoskeleton organization;axon development;postsynaptic intermediate filament cytoskeleton organization;regulation of organelle transport along microtubule;cellular response to leukemia inhibitory factor
Cellular component: cytoplasm;cytoskeleton;neurofilament;postsynaptic density;axon;myelin sheath;neurofibrillary tangle;Schaffer collateral - CA1 synapse;postsynaptic intermediate filament cytoskeleton
Molecular function: structural molecule activity;structural constituent of cytoskeleton;microtubule binding;kinesin binding;protein kinase binding;protein binding, bridging;dynein complex binding;structural constituent of postsynaptic intermediate filament cytoskeleton