KIF11

protein-coding

kinesin family member 11, the group of Kinesins

Gene summary

This gene encodes a motor protein that belongs to the kinesin-like protein family. Members of this protein family are known to be involved in various kinds of spindle dynamics. The function of this gene product includes chromosome positioning, centrosome separation and establishing a bipolar spindle during cell mitosis. [provided by RefSeq, Jul 2008]

Previous symbols:

KNSL1

MANE transcript

NM_004523.4

Inheritance

ClinVar variants

P:218U:342B:261

Top phenotype

Microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual development

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr10:92,574,105-92,655,395

External References & Databases

Ensembl (ENSG00000138160)

Transcript & Mutation Effects

hg38 • Region Span ~81.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual developmentSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007918

Submitter: PanelApp Australia

microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual developmentDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007918

Submitter: G2P

microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual developmentSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007918

Submitter: Ambry Genetics

microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual developmentSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007918

Submitter: Orphanet

microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual developmentDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007918

Submitter: ClinGen

Variants in KIF11 were first associated with autosomal dominant inheritance of Microcephaly, lymphedema, chorioretinopathy syndrome, MCLMR, in 2012 (Ostergaard et al., 22284827). Over 16 probands reported unique heterozygous variants in this gene including five frameshift, three missense variants in highly conserved amino acid residues, two large deletions covering entire exons, two canonical splice site variants, as well as four stop gained. De novo variants were reported in six probands in two publications (Ostergaard et al., 22284827; Hull et al., 31077665). In addition, variants segregate in five additional family members in a large multi-generational pedigree (Ostergaard et al., 22284827). This gene-disease association is supported by expression studies which show expression in the retinal pigment epithelium, the inner segment, and the ciliary region of the photoreceptor layer, and the outer plexiform layers. Additional localization studies with markers specific for cilium and centrioles show expression in centrioles, basal bodies, and the connecting cilia of photoreceptor cells (Birtel et al., 28785766), however the role in retinal biology is still unknown. This gene has also been implicated in familial exudative vitreoretinopathy, FEVR, associated with microcephaly with overlapping clinical features (Hull et al., 31077665). More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence (12.5 pts.) has been reached. In summary, KIF11 is definitively associated with autosomal dominant MCLRD, and this has been has been upheld over time.

ciliopathyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0005308

Submitter: Ambry Genetics

microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual developmentSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007918

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual developmentAD

Manifestation: Cardiovascular; Craniofacial; 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

Refs: 15930898; 22653704; 22284827; 25115524

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KIF11 variants in ClinVar

26 Conditions Cataloged

not providedTotal: 829

not specifiedTotal: 157

Microcephaly with or without chorioretinopathy, lymphedema, or intellectual disabilityTotal: 135

KIF11-related disorderTotal: 127

Inborn genetic diseasesTotal: 90

Retinal dystrophyTotal: 9

MicrocephalyTotal: 2

Intellectual disabilityTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004523.4. 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	2 clinvar		4 clinvar	177 clinvar	3 clinvar	186
missense		13 clinvar	326 clinvar	79 clinvar	2 clinvar	420
nonsense	34 clinvar	21 clinvar	2 clinvar			57
start loss	2 clinvar	1 clinvar				3
frameshift	70 clinvar	44 clinvar	3 clinvar			117
splice donor/acceptor (+/-2bp)	15 clinvar	16 clinvar	7 clinvar			38
Total	123	95	342	256	5	821

Highest pathogenic variant AF is 0.0000014060109

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004523.4	RefSeq	NP_004514.2	22	MANE Select
ENST00000260731.5	Ensembl	ENSP00000260731.3	22	MANE Select
ENST00000676621.1	Ensembl	ENSP00000503639.1	13	Standard
ENST00000676647.1	Ensembl	ENSP00000503394.1	21	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
kif11	Danio rerio	Structure: radial glial cell Quality: has fewer parts of type abnormal

Gene / Model

Organism

Observed Phenotype

kif11

Danio rerio

Structure: radial glial cell

Quality: has fewer parts of type

abnormal

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

mitotic cell cycle
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum
microtubule-based movement
spindle organization
mitotic spindle organization

Molecular Function

microtubule motor activity
ATP binding
microtubule binding
ATP-dependent microtubule motor activity, plus-end-directed
ATPase activity

Cellular Component

spindle pole
nucleus
spindle
cytosol
kinesin complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000260731
Coding exons: 22
Length: 62108
Individuals with no LoFs: 125711
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125717
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.27	310	520	0.596	0.0000257	6946
Missense (PolyPhen)		41	162.32	0.25258		1997
Synonymous	0.623	172	183	0.941	0.00000845	1980
Loss of Function	6.43	2	52.1	0.0384	0.00000268	697

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00013	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000028	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Motor protein required for establishing a bipolar spindle during mitosis (PubMed:19001501). Required in non-mitotic cells for transport of secretory proteins from the Golgi complex to the cell surface (PubMed:23857769). {ECO:0000269|PubMed:19001501, ECO:0000269|PubMed:23857769}.;
Disease: DISEASE: Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) [MIM:152950]: An autosomal dominant disorder that involves an overlapping but variable spectrum of central nervous system and ocular developmental anomalies. Microcephaly ranges from mild to severe and is often associated with mild to moderate developmental delay and a characteristic facial phenotype with upslanting palpebral fissures, broad nose with rounded tip, long philtrum with thin upper lip, prominent chin, and prominent ears. Chorioretinopathy is the most common eye abnormality, but retinal folds, microphthalmia, and myopic and hypermetropic astigmatism have also been reported, and some individuals have no overt ocular phenotype. Congenital lymphedema, when present, is typically confined to the dorsa of the feet, and lymphoscintigraphy reveals the absence of radioactive isotope uptake from the webspaces between the toes. {ECO:0000269|PubMed:22284827}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.134

Intolerance Scores

LoFtool: 0.0258
RVIS EVS: 0.07
RVIS percentile EVS: 58.96

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.784

Gene Damage Prediction

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