KIF5A

kinesin family member 5A, the group of Kinesins

Basic information

Region (hg38): 12:57546025-57586633

Previous symbols: [ "SPG10" ]

Links

ENSG00000155980 ∙ NCBI:3798 ∙ OMIM:602821 ∙ HGNC:6323 ∙ Uniprot:Q12840 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hereditary spastic paraplegia 10 (Strong), mode of inheritance: AD
• myoclonus, intractable, neonatal (Limited), mode of inheritance: AD
• hereditary spastic paraplegia 10 (Strong), mode of inheritance: AD
• hereditary spastic paraplegia 10 (Supportive), mode of inheritance: AD
• autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation (Supportive), mode of inheritance: AD
• amyotrophic lateral sclerosis, susceptibility to, 25 (Definitive), mode of inheritance: AD
• myoclonus, intractable, neonatal (Moderate), mode of inheritance: AD
• myoclonus, intractable, neonatal (Definitive), mode of inheritance: AD
• hereditary spastic paraplegia 10 (Strong), mode of inheritance: AD
• myoclonus, intractable, neonatal (Strong), mode of inheritance: AD
• amyotrophic lateral sclerosis, susceptibility to, 25 (Strong), mode of inheritance: AD
• amyotrophic lateral sclerosis, susceptibility to, 25 (Definitive), mode of inheritance: AD
• inherited neurodegenerative disorder (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Neonatal intractable myoclonus (NEIMY); Spastic paraplegia 10, autosomal dominant; Amyotrophic lateral sclerosis, susceptibility to, 25	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	Biochemical; Neurologic; Ophthalmologic	10441583; 12355402; 15452312; 16489470; 16476820; 18245137; 18853458; 21107874; 21623771; 22788249; 25008398; 27414745; 27463701; 29342275; 29566793

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the KIF5A gene.

• Spastic paraplegia (840 variants)
• not provided (244 variants)
• Hereditary spastic paraplegia 10 (115 variants)
• not specified (46 variants)
• Hereditary spastic paraplegia (42 variants)
• Inborn genetic diseases (22 variants)
• Myoclonus, intractable, neonatal (10 variants)
• KIF5A-related condition (9 variants)
• Amyotrophic lateral sclerosis, susceptibility to, 25 (4 variants)
• Spastic paraplegia, autosomal dominant (3 variants)
• Amyotrophic lateral sclerosis (3 variants)
• KIF5A-Related Disorders (2 variants)
• Demyelinating peripheral neuropathy (2 variants)
• Myoclonus, intractable, neonatal;Hereditary spastic paraplegia 10;Amyotrophic lateral sclerosis, susceptibility to, 25 (1 variants)
• Auditory neuropathy (1 variants)
• Inherited neurodegenerative disorder (1 variants)
• Peripheral neuropathy (1 variants)
• Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 (1 variants)
• Hereditary spastic paraplegia 10;Myoclonus, intractable, neonatal;Amyotrophic lateral sclerosis, susceptibility to, 25 (1 variants)
• Myoclonus, intractable, neonatal;Amyotrophic lateral sclerosis, susceptibility to, 25;Hereditary spastic paraplegia 10 (1 variants)
• KIF5A-related amyotrophic lateral sclerosis (1 variants)
• Hereditary spastic paraplegia 10;Amyotrophic lateral sclerosis, susceptibility to, 25;Myoclonus, intractable, neonatal (1 variants)
• Paroxysmal dyskinesia (1 variants)
• KIF5A-related intractable neonatal myoclonus (1 variants)
• Charcot-Marie-Tooth disease type 2 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the KIF5A 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			9	196	6	211
missense	11	21	325	52	1	410
nonsense	4	3	4			11
start loss			2			2
frameshift	5	3	7			15
inframe indel		1	8			9
splice donor/acceptor (+/-2bp)	2	4	4			10
splice region			34	47	3	84
non coding			26	176	39	241
Total	22	32	385	424	46

Highest pathogenic variant AF is 0.0000263

Variants in KIF5A

This is a list of pathogenic ClinVar variants found in the KIF5A region.

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

Position	Type	Phenotype	Significance	ClinVar
12-57547045-C-A			Uncertain significance (Jul 01, 2021)
12-57549736-C-T			Benign (Aug 03, 2018)
12-57549925-A-G			Likely benign (Sep 08, 2019)
12-57549977-C-T			Likely benign (Sep 20, 2019)
12-57550079-G-A		Spastic paraplegia, autosomal dominant	Uncertain significance (Jun 14, 2016)
12-57550227-C-T		Hereditary spastic paraplegia 10	Uncertain significance (Jan 13, 2018)
12-57550259-G-A		not specified	Likely benign (Mar 14, 2017)
12-57550268-CACCATGGCGGAGACCA-C		Spastic paraplegia	Uncertain significance (Apr 13, 2022)
12-57550274-G-A		Spastic paraplegia	Uncertain significance (Jun 28, 2022)
12-57550275-GC-AA		Spastic paraplegia	Uncertain significance (Nov 23, 2022)
12-57550276-C-T		Spastic paraplegia • Inborn genetic diseases	Uncertain significance (Oct 17, 2023)
12-57550277-G-C		Spastic paraplegia	Likely benign (Oct 11, 2022)
12-57550284-A-G		Spastic paraplegia	Uncertain significance (Jan 05, 2023)
12-57550293-T-C		Spastic paraplegia	Uncertain significance (Nov 27, 2023)
12-57550294-G-T		KIF5A-related disorder	Uncertain significance (Aug 03, 2023)
12-57550299-A-G		Spastic paraplegia	Uncertain significance (Jun 04, 2021)
12-57550301-C-A		Spastic paraplegia	Likely benign (Jun 28, 2023)
12-57550303-A-C		Spastic paraplegia	Uncertain significance (Sep 04, 2023)
12-57550308-C-G		Spastic paraplegia	Uncertain significance (Jan 01, 2022)
12-57550312-G-A		Spastic paraplegia	Uncertain significance (Mar 31, 2023)
12-57550313-C-T		Spastic paraplegia	Likely benign (Mar 29, 2022)
12-57550314-C-T		Spastic paraplegia	Pathogenic (Jan 24, 2024)
12-57550320-C-T			Uncertain significance (Feb 05, 2020)
12-57550322-G-T		Spastic paraplegia	Likely benign (Dec 22, 2022)
12-57550323-C-T		Spastic paraplegia	Uncertain significance (Oct 16, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
KIF5A	protein_coding	protein_coding	ENST00000455537	28	36635

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.0000494	125738	0	10	125748	0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.60	341	586	0.582	0.0000378	6792
Missense in Polyphen		74	201.85	0.36661		2385
Synonymous	0.850	217	234	0.929	0.0000150	1932
Loss of Function	6.44	8	63.3	0.126	0.00000371	734

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.000163	0.000163
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000440	0.0000439
Middle Eastern	0.000163	0.000163
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Microtubule-dependent motor required for slow axonal transport of neurofilament proteins (NFH, NFM and NFL). Can induce formation of neurite-like membrane protrusions in non-neuronal cells in a ZFYVE27-dependent manner. The ZFYVE27-KIF5A complex contributes to the vesicular transport of VAPA, VAPB, SURF4, RAB11A, RAB11B and RTN3 proteins in neurons. Required for anterograde axonal transportation of MAPK8IP3/JIP3 which is essential for MAPK8IP3/JIP3 function in axon elongation. {ECO:0000250|UniProtKB:P33175, ECO:0000250|UniProtKB:Q6QLM7}.
• Disease: DISEASE: Spastic paraplegia 10, autosomal dominant (SPG10) [MIM:604187]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. {ECO:0000269|PubMed:12355402, ECO:0000269|PubMed:15452312, ECO:0000269|PubMed:16476820, ECO:0000269|PubMed:16489470, ECO:0000269|PubMed:18203753, ECO:0000269|PubMed:18245137, ECO:0000269|PubMed:18853458, ECO:0000269|PubMed:21107874}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myoclonus, intractable, neonatal (NEIMY) [MIM:617235]: An autosomal dominant neurologic disorder characterized by severe, infantile-onset myoclonic seizures, hypotonia, optic nerve abnormalities, dysphagia, apnea, and early developmental arrest. Brain imaging shows a progressive leukoencephalopathy. Some patients may die in infancy. {ECO:0000269|PubMed:24215330, ECO:0000269|PubMed:27414745, ECO:0000269|PubMed:27463701}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Amyotrophic lateral sclerosis 25 (ALS25) [MIM:617921]: A form of amyotrophic lateral sclerosis, 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. ALS25 is an autosomal dominant form with variable adult onset and incomplete penetrance. {ECO:0000269|PubMed:29342275, ECO:0000269|PubMed:29566793}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. The mutation NM_004984.2:c.33019A>G encoding the predicted missence variant p.Arg1007Gly, may also affect splicing and induce the skipping of exon 27, resulting in a frameshift and a premature stop codon producing a truncated protein p.Asn999Valfs*39. {ECO:0000269|PubMed:29342275}.
• Pathway: Dopaminergic synapse - Homo sapiens (human);Endocytosis - Homo sapiens (human);Signal Transduction;Vesicle-mediated transport;Membrane Trafficking;RHO GTPases activate KTN1;Kinesins;Factors involved in megakaryocyte development and platelet production;RHO GTPase Effectors;Signaling by Rho GTPases;Hemostasis;COPI-dependent Golgi-to-ER retrograde traffic;Golgi-to-ER retrograde transport;Intra-Golgi and retrograde Golgi-to-ER traffic (Consensus)

Recessive Scores

• pRec: 0.171

Intolerance Scores

• loftool: 0.0960
• rvis_EVS: -1.31
• rvis_percentile_EVS: 4.88

Haploinsufficiency Scores

• pHI: 0.409
• hipred: Y
• hipred_score: 0.685
• ghis: 0.603

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.668

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Kif5a
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region 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); 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); normal phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype

Zebrafish Information Network

• Gene name: kif5aa
• Affected structure: retinal ganglion cell
• Phenotype tag: abnormal
• Phenotype quality: decreased occurrence

Gene ontology

• Biological process: retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum;microtubule-based movement;chemical synaptic transmission;axon guidance;vesicle-mediated transport;antigen processing and presentation of exogenous peptide antigen via MHC class II;synaptic vesicle transport;anterograde dendritic transport of neurotransmitter receptor complex;anterograde axonal protein transport;retrograde neuronal dense core vesicle transport
• Cellular component: cytosol;kinesin complex;microtubule;membrane;dendrite cytoplasm;ciliary rootlet;neuronal cell body;synapse;perinuclear region of cytoplasm;axon cytoplasm
• Molecular function: motor activity;microtubule motor activity;protein binding;ATP binding;microtubule binding;ATP-dependent microtubule motor activity, plus-end-directed;ATPase activity;kinesin binding