KIF21A
protein-codingkinesin family member 21A, the group of Kinesins|WD repeat domain containing
Gene summary
This gene encodes a member of the KIF4 subfamily of kinesin-like motor proteins. The encoded protein is characterized by an N-terminal motor domain a coiled-coil stalk domain and a C-terminal WD-40 repeat domain. This protein may be involved in microtubule dependent transport. Mutations in this gene are the cause of congenital fibrosis of extraocular muscles-1. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Mar 2010]
- FEOM1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~150.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0021083
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AD
Disease ID:MONDO:0021083
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007614
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0021083
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0021083
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0015168
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0800209
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0021083
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007614
Submitter: ClinGen
KIF21A was first reported in relation to autosomal dominant congenital fibrosis of the extraocular muscles (CFEOM) in 2003 (Yamada et al., PMID:14595441). CFEOM is a syndrome of congenital nonprogressive bilateral ophthalmoplegia affecting the extraocular muscles innervated by the oculomotor and/or trochlear nerves. Classic presentations of CFEOM are characterized by ptosis, severe limitation of vertical gaze, and inability to raise either eye above the midline with variable limitation of the horizontal gaze. This disorder has historically been referred to as both CFEOM1 and CFEOM3, the latter characterized by a milder, sometimes unilateral presentation.Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, CFEOM1 (OMIM:135700) and CFEOM3 (OMIM:135700). Evidence supporting this gene-disease relationship includes case-level, segregation, and experimental data. Eleven missense variants reported across 33 probands in seven publications (PMIDs: 14595441,15621877, 15621876, 18332320, 15223798, 19551685, 17511870) are included in this curation. Of the variants reported in this curation, all were absent from gnomAD and the most frequent variant (R954W) was reported in 21 probands, 9 of which were de novo observations. This specific variant is the most common for this syndrome, and variants at this residue (R954) account for the majority of cases. This residue has been shown to contain a CpG dinucleotide that is methylated, providing some insight into the high mutability of this region in KIF21A (PMID:15621877). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be gain of function. This gene-disease relationship is also supported by animal models and expression studies (PMIDs:24656932, 22465342). Knock-in mice containing the R954W variant have been shown to exhibit CFEOM phenotypes with minimal differences, and KIF21A has been shown to be expressed normally in human and murine extraocular and skeletal muscle cells. In summary, KIF21A is definitively associated with autosomal dominant CFEOM. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Brain Malformations Expert Panel on the meeting date 09/28/21 (SOP Version 8).
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal
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 KIF21A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001173464.2. 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 | 7 | 32 | 12 | 51 | ||
| missense | 5 | 7 | 236 | 25 | 10 | 283 |
| nonsense | 2 | 3 | 5 | |||
| start loss | 0 | |||||
| frameshift | 1 | 3 | 4 | |||
| splice donor/acceptor (+/-2bp) | 1 | 13 | 14 | |||
| Total | 6 | 10 | 262 | 57 | 22 | 357 |
Highest pathogenic variant AF is 6.842697e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001166935.1 | 38 | MANE Select | |
| Ensembl | ENSP00000354878.5 | 38 | MANE Select | |
| RefSeq | NP_001166934.1 | 34 | Standard | |
| RefSeq | NP_001166936.1 | 34 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Vesicle-mediated transport
- Membrane Trafficking
- Kinesins
- Factors involved in megakaryocyte development and platelet production
- Hemostasis
Biological Process
- microtubule-based movement
Molecular Function
- microtubule motor activity
- protein binding
- ATP binding
- microtubule binding
- ATPase activity
Cellular Component
- cytosol
- kinesin complex
- microtubule
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000361418
- Coding exons
- 38
- Length
- 150163
- Individuals with no LoFs
- 125660
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 88
- Defined
- 125748
- p
- 0.000350
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.65 | 650 | 870 | 0.747 | 0.0000444 | 11019 |
| Missense (PolyPhen) | 219 | 345.29 | 0.63425 | 4302 | ||
| Synonymous | 0.261 | 293 | 299 | 0.981 | 0.0000150 | 3132 |
| Loss of Function | 5.88 | 31 | 91.8 | 0.338 | 0.00000497 | 1130 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.00020 | 0.00020 | rare |
| Ashkenazi Jewish | 0.00020 | 0.00020 | rare |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.00030 | 0.00030 | rare |
| South Asian | 0.0011 | 0.0011 | notable |
| Other | 0.00017 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Microtubule-binding motor protein probably involved in neuronal axonal transport. In vitro, has a plus-end directed motor activity (By similarity). {ECO:0000250}.;
- Disease
- DISEASE: Fibrosis of extraocular muscles, congenital, 1 (CFEOM1) [MIM:135700]: A congenital ocular motility disorder marked by restrictive ophthalmoplegia affecting extraocular muscles innervated by the oculomotor and/or trochlear nerves. It is clinically characterized by anchoring of the eyes in downward gaze, ptosis, and backward tilt of the head. Patients affected by congenital fibrosis of extraocular muscles type 1 show an absence of the superior division of the oculomotor nerve (cranial nerve III) and corresponding oculomotor subnuclei. {ECO:0000269|PubMed:14595441, ECO:0000269|PubMed:16157808, ECO:0000269|PubMed:17511870, ECO:0000269|PubMed:24715754}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.139
Intolerance Scores
- LoFtool
- 0.856
- RVIS EVS
- -0.15
- RVIS percentile EVS
- 42.34
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.466
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |