STIL

protein-coding

STIL centriolar assembly protein

Gene summary

This gene encodes a cytoplasmic protein implicated in regulation of the mitotic spindle checkpoint, a regulatory pathway that monitors chromosome segregation during cell division to ensure the proper distribution of chromosomes to daughter cells. The protein is phosphorylated in mitosis and in response to activation of the spindle checkpoint, and disappears when cells transition to G1 phase. It interacts with a mitotic regulator, and its expression is required to efficiently activate the spindle checkpoint. It is proposed to regulate Cdc2 kinase activity during spindle checkpoint arrest. Chromosomal deletions that fuse this gene and the adjacent locus commonly occur in T cell leukemias, and are thought to arise through illegitimate V-(D)-J recombination events. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

MANE transcript

NM_001048166.1

Inheritance

ClinVar variants

P:31U:248B:92

Top phenotype

Microcephaly, primary autosomal recessive, 7

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr1:47,250,139-47,314,892

External References & Databases

Ensembl (ENSG00000123473)

Transcript & Mutation Effects

hg38 • Region Span ~64.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

microcephaly 7, primary, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012989

Submitter: PanelApp Australia

autosomal recessive primary microcephalyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016660

Submitter: ClinGen

STIL was first reported in relation to autosomal recessive primary microcephaly in 2009 (Kumar et al., PMID: 19215732). Thirteen variants (5 missense, 2 splice-disrupting, 2 frameshifts, and 4 premature termination codons in the last exon) that have been reported in twelve probands in eight publications (PMIDs: 19215732, 22989186, 24986681, 25218063, 25658757, 29230157, 30214071, 32677750) are included in this curation. Ten of these twelve probands were homozygous variant carriers in consanguineous families, many of which had more than one affected homozygote. Six individuals from four families in which brain imaging had been performed had a variety of brain malformations, including several cases consistent with holoprosencephaly (PMID 24986681, 25218063, 25658757, 29230157). The mechanism of pathogenicity is unknown; although an AR condition, a lack of true LoF homozygotes suggest the possibility of lethality for complete absence of gene product. This gene-disease association is also supported by a STIL -/- mouse model, which shows axial midline defects and embryonic lethality (PMID 10385121). Functional studies show STIL-/- mouse embryonic fibroblasts lack centrioles and primary cilia and are rescued by introduction of exogenous STIL; introduction of STIL carrying observed human mutations allowed partial rescue (PMID 25486474). In summary, STIL is definitively associated with autosomal recessive primary microcephaly. 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 gene curation expert panel on 28.Mar.2023.

autosomal recessive primary microcephalySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016660

Submitter: Orphanet

microcephaly 7, primary, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012989

Submitter: G2P

microcephaly 7, primary, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012989

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Microcephaly, primary autosomal recessive, 7AR

Manifestation: Neurologic

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: 19215732; 20978018; 25218063

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to STIL variants in ClinVar

8 Conditions Cataloged

not providedTotal: 220

Inborn genetic diseasesTotal: 145

Microcephaly 7, primary, autosomal recessiveTotal: 108

not specifiedTotal: 43

STIL-related disorderTotal: 18

Abnormal brain morphologyTotal: 2

Myoepithelial tumorTotal: 1

Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001048166.1. 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			13 clinvar	66 clinvar	1 clinvar	80
missense	2 clinvar	4 clinvar	229 clinvar	23 clinvar	2 clinvar	260
nonsense	4 clinvar	3 clinvar	2 clinvar			9
start loss						0
frameshift	5 clinvar	8 clinvar	3 clinvar			16
splice donor/acceptor (+/-2bp)	2 clinvar	3 clinvar	1 clinvar			6
Total	13	18	248	89	3	371

Highest pathogenic variant AF is 0.000039662176

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 93 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001048166.1	RefSeq	NP_001041631.1	16	MANE Select
ENST00000371877.8	Ensembl	ENSP00000360944.3	16	MANE Select
NM_001282936.1	RefSeq	NP_001269865.1	16	Standard
NM_001282937.1	RefSeq	NP_001269866.1	16	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
stil	Danio rerio	Structure: cell Quality: absent abnormal

Gene / Model

Organism

Observed Phenotype

stil

Danio rerio

Structure: cell

Quality: absent

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signaling events mediated by the Hedgehog family

Biological Process

embryonic axis specification
in utero embryonic development
neural tube closure
heart looping
mitotic spindle organization

Molecular Function

protein binding
identical protein binding

Cellular Component

cytoplasm
centrosome
centriole
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000371877
Coding exons: 16
Length: 64009
Individuals with no LoFs: 125728
Homozygous LoFs: 0
Heterozygous LoFs: 20
Defined: 125748
p: 0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.13	587	669	0.878	0.0000329	8535
Missense (PolyPhen)		159	193.5	0.8217		2479
Synonymous	1.54	210	240	0.874	0.0000127	2438
Loss of Function	5.04	12	50.8	0.236	0.00000253	669

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000097	0.000097	rare
South Asian	0.000065	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Immediate-early gene. Plays an important role in embryonic development as well as in cellular growth and proliferation; its long-term silencing affects cell survival and cell cycle distribution as well as decreases CDK1 activity correlated with reduced phosphorylation of CDK1. Plays a role as a positive regulator of the sonic hedgehog pathway, acting downstream of PTCH1 (PubMed:16024801, PubMed:9372240). Plays an important role in the regulation of centriole duplication. Required for the onset of procentriole formation and proper mitotic progression. During procentriole formation, is essential for the correct loading of SASS6 and CENPJ to the base of the procentriole to initiate procentriole assembly (PubMed:22020124). {ECO:0000269|PubMed:16024801, ECO:0000269|PubMed:22020124, ECO:0000269|PubMed:9372240}.;
Disease: DISEASE: Note=A chromosomal aberration involving STIL may be a cause of some T-cell acute lymphoblastic leukemias (T-ALL). A deletion at 1p32 between STIL and TAL1 genes leads to STIL/TAL1 fusion mRNA with STIL exon 1 splicing to TAL1 exon 3. As both STIL exon 1 and TAL1 exon 3 are 5'-untranslated exons, STIL/TAL1 fusion mRNA predicts a full-length TAL1 protein under the control of the STIL promoter, leading to inappropriate TAL1 expression. In childhood T-cell malignancies (T-ALL), a type of defect such as STIL/TAL1 fusion is associated with a good prognosis. In cultured lymphocytes from healthy adults, STIL/TAL1 fusion mRNA may be detected after 7 days of culture. {ECO:0000269|PubMed:11390401, ECO:0000269|PubMed:12681356, ECO:0000269|PubMed:1311214, ECO:0000269|PubMed:14504110, ECO:0000269|PubMed:1922059, ECO:0000269|PubMed:2209547, ECO:0000269|PubMed:2255914}.; DISEASE: Microcephaly 7, primary, autosomal recessive (MCPH7) [MIM:612703]: A disease defined as a head circumference more than 3 standard deviations below the age-related mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. Despite this marked reduction in size, the gyral pattern is relatively well preserved, with no major abnormality in cortical architecture. Affected individuals are mentally retarded. Primary microcephaly is further defined by the absence of other syndromic features or significant neurological deficits due to degenerative brain disorder. {ECO:0000269|PubMed:19215732, ECO:0000269|PubMed:22989186}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0886

Intolerance Scores

LoFtool: 0.754
RVIS EVS: 0.69
RVIS percentile EVS: 85.29

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.0797

Gene Damage Prediction

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