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 (3 variants)
• Charcot-Marie-Tooth disease axonal type 2CC (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.

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			2	223	18	243
missense			404	25	11	440
nonsense		1	13	1	1	16
start loss			2			2
frameshift	3	2	24	3		32
inframe indel			28	6	3	37
splice donor/acceptor (+/-2bp)		1	1			2
splice region			3	5		8
non coding			3	18	22	43
Total	3	4	477	276	55

Variants in NEFH

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

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

Position	Type	Phenotype	Significance	ClinVar
22-29480260-G-A			Uncertain significance (Sep 23, 2022)
22-29480263-A-C			Uncertain significance (May 12, 2023)
22-29480264-T-C			Uncertain significance (Jan 25, 2023)
22-29480266-A-G			Uncertain significance (Nov 03, 2021)
22-29480274-C-T			Likely benign (Oct 09, 2023)
22-29480276-G-C		Inborn genetic diseases • NEFH-related disorder	Uncertain significance (Jul 05, 2023)
22-29480277-C-T		NEFH-related disorder	Likely benign (Sep 10, 2022)
22-29480282-C-A			Uncertain significance (Aug 20, 2022)
22-29480283-G-A			Benign (Jun 01, 2024)
22-29480287-G-C		Charcot-Marie-Tooth disease axonal type 2CC	Uncertain significance (Mar 27, 2018)
22-29480289-G-A			Likely benign (Feb 01, 2024)
22-29480295-G-T			Likely benign (Feb 16, 2023)
22-29480296-G-A			Uncertain significance (Jan 10, 2023)
22-29480297-G-A		Inborn genetic diseases	Uncertain significance (Mar 01, 2022)
22-29480298-C-A			Likely benign (May 28, 2022)
22-29480299-G-GC		Charcot-Marie-Tooth disease axonal type 2CC	Conflicting classifications of pathogenicity (Jul 03, 2023)
22-29480300-C-T			Uncertain significance (Jul 16, 2021)
22-29480303-C-G			Uncertain significance (Sep 10, 2023)
22-29480304-G-A			Likely benign (Jun 27, 2023)
22-29480309-C-A		Inborn genetic diseases • not specified	Conflicting classifications of pathogenicity (Mar 12, 2024)
22-29480312-C-T			Benign (Apr 11, 2022)
22-29480322-C-G			Likely benign (May 09, 2022)
22-29480323-G-A			Uncertain significance (Nov 17, 2023)
22-29480323-G-T		NEFH-related disorder	Uncertain significance (Jul 05, 2024)
22-29480324-G-A			Uncertain significance (Sep 29, 2022)

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