KIF5A
protein-codingkinesin family member 5A, the group of Kinesins
Gene summary
This gene encodes a member of the kinesin family of proteins. Members of this family are part of a multisubunit complex that functions as a microtubule motor in intracellular organelle transport. Mutations in this gene cause autosomal dominant spastic paraplegia 10. [provided by RefSeq, Jul 2008]
- SPG10
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~40.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0011408
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0060670
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014979
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0011408
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0011408
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0011408
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014979
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0060670
Submitter: ClinGen
KIF5A was first reported in relation to autosomal dominant inherited ALS in two separate studies both published in March 2018 (Brenner et al., PMID: 29342275 and Nicolas et al., PMID: 29566793). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found difference in molecular mechanism and phenotypic variability of Hereditary Spastic Paraplegia and Charcot-Marie-Tooth disease type 2. Therefore, the following disease entities have been split into multiple disease entities, ALS 25 (OMIM:617921), Spastic paraplegia 10 (OMIM:604187) and Charcot-Marie-Tooth disease type 2. 42 variants (variant type, missense, frameshift and exon skipping) that have been reported in 42 probands in 8 publications (PMIDs: 29342275, 29566793, 30301576, 31422367, 31475037, 32815063, 32888732, 33077544) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Many of the variants reported in people with ALS are at the C-terminal end of the protein and involve either skipping of exon 27 or frameshift variants that cause the final 34 amino acids of the protein to be substituted for a novel sequence of 39 or more amino acids with a number of charged residues. This novel amino acid sequence appears to confer a toxic gain of function of the variant protein (PMIDs: 35430760, 35385738). Cellular functional evidence includes reduced survival of neurons, formation of toxic aggregates, mislocalisation of variant protein to the distal end of neurons, increased binding and activity on microtubules, lack of autoinhibition, and co-localisation and subsequent mislocalisation of wild-type protein. The evidence was considered strong and well replicated enough to upgrade the variant score to one for each first occurrence of a variant predicted to cause the tail domain toxic gain of function. This gene-disease relationship is also supported by experimental evidence, including expression assays (PMIDs: 24309898, 23006449) showing that KIF5A is expressed in healthy motor neurons and the levels are reduced in people with ALS. A model of C. elegans expressing human wild-type and exon 27 skipping KIF5A demonstrated neuronal loss and abnormal phenotype (PMID: 35430760). There are several mouse models of KIF5A knock-out in neurons (eg PMIDs: 12682084, 22466687), these were included in the curation but not scored as the mechanism is likely to be gain-of-function. In summary, KIF5A is definitively associated with autosomal dominant ALS. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0060670
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014979
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0060670
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0014979
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0017940
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0024237
Submitter: ClinGen
KIF5A was first linked to hereditary spastic paraplegia (SPG10) in 2002. However, over time the phenotypic spectrum of KIF5A has broadened to include disorders such as pure & complex HSP, autosomal dominant Charcot-Marie-Tooth type 2 (CMT2), Amyotrophic Lateral Sclerosis (ALS) and neonatal intractable myoclonus (NEIMY). Due to differences in phenotype and genotype clustering, we split ALS and NEIMY. However, the HSP and CMT2 phenotypes have suspicious genetic and phenotypic overlap. Variants in the motor domain of KIF5A have been presented as causing pure & complex HSP as well as CMT2. In some cases, the intra-familial variability of a variant can assign a primarily HSP phenotype without neuropathy to one sibling, and CMT2 with pyramidal signs to another. For these reasons, we have decided to lump SPG10 and CMT2. In this curation, we scored 10 variants from 10 families as well as segregation by linkage analysis to collect a genetic evidence score of 8 (PMID: 25008398, 18853458, 12355402). There were two animal models studied for KIF5A mutations. A (-/-) KIF5A mouse showed an axonal transport deficit affecting motor neurons more seriously than sensory neurons. A N256S drosophila HSP model also induced axonal transport and motor neuron disease. The results of these studies suggested a dominant-negative action of mutant KIF5A on the kinesin-1 complex. These animal models as well as functional evidence (immunoblot) scored 4.5 points of experimental evidence (PMID :10964943, 22466687, 23209432). These tally to 12.5 points: definitive with replication over time. While literature suggests the primary manifestation of mutations in this gene is HSP, there have been many cases, where the clinical presentation is CMT2, potentially with subclinical signs of HSP. It is likely that KIF5A mutations infer a continuum of phenotypic manifestations and signs for complex HSP and CMT2 should be studied in patients. In summary, KIF5A is definitively associated with autosomal dominant HSP and CMT2.
Inheritance Pattern: AD
Disease ID:MONDO:0014979
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011408
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Neurologic; Ophthalmologic
Intervention: General
Rationale: 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to KIF5A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004984.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 14 | 312 | 5 | 331 | ||
| missense | 11 | 42 | 527 | 103 | 6 | 689 |
| nonsense | 8 | 15 | 1 | 24 | ||
| start loss | 3 | 3 | ||||
| frameshift | 14 | 9 | 5 | 28 | ||
| splice donor/acceptor (+/-2bp) | 3 | 14 | 5 | 22 | ||
| Total | 36 | 80 | 555 | 415 | 11 | 1097 |
Highest pathogenic variant AF is 0.000011155194
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004975.2 | 28 | MANE Select | |
| Ensembl | ENSP00000408979.2 | 28 | MANE Select | |
| RefSeq | NP_001341634.1 | 25 | Standard | |
| Ensembl | ENSP00000286452.5 | 25 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| kif5aa | Danio rerio | Structure: retinal ganglion cell Quality: decreased occurrence abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Dopaminergic synapse - Homo sapiens (human)
- Endocytosis - Homo sapiens (human)
- Signal Transduction
- Vesicle-mediated transport
- Membrane Trafficking
Biological Process
- retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum
- microtubule-based movement
- chemical synaptic transmission
- axon guidance
- vesicle-mediated transport
Molecular Function
- motor activity
- microtubule motor activity
- protein binding
- ATP binding
- microtubule binding
Cellular Component
- cytosol
- kinesin complex
- microtubule
- membrane
- dendrite cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000455537
- Coding exons
- 28
- Length
- 36635
- Individuals with no LoFs
- 125738
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 10
- Defined
- 125748
- p
- 0.0000398
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.60 | 341 | 586 | 0.582 | 0.0000378 | 6792 |
| Missense (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 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000044 | 0.000044 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- 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}.;
Recessive Scores
- pRec
- 0.171
Intolerance Scores
- LoFtool
- 0.0960
- RVIS EVS
- -1.31
- RVIS percentile EVS
- 4.88
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.668
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |