GeneBe

SKI

protein-coding

SKI proto-oncogene, the group of SKI transcriptional corepressors

Gene summary

This gene encodes the nuclear protooncogene protein homolog of avian sarcoma viral (v-ski) oncogene. It functions as a repressor of TGF-beta signaling, and may play a role in neural tube development and muscle differentiation. [provided by RefSeq, Oct 2009]

MANE transcript

NM_003036.4

Inheritance

AD

ClinVar variants

P:34U:645B:651

Top phenotype

Shprintzen-Goldberg craniosynostosis syndrome

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr1:2,227,388-2,310,213

External References & Databases

Ensembl (ENSG00000157933)NCBI Gene (6497)OMIM (164780)HGNC:10896GenCCUniProt (P12755)AlphaFoldClinVar (SKI)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~82.8 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Shprintzen-Goldberg syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008426

Submitter: Ambry Genetics

Shprintzen-Goldberg syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008426

Submitter: Genomics England PanelApp

Shprintzen-Goldberg syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008426

Submitter: Orphanet

Shprintzen-Goldberg syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008426

Submitter: PanelApp Australia

Shprintzen-Goldberg syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008426

Submitter: G2P

Shprintzen-Goldberg syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008426

Submitter: Labcorp Genetics (formerly Invitae)

Shprintzen-Goldberg syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008426

Submitter: ClinGen

SKI was first reported in relation to Shprintzen-Goldberg syndrome (SGS) as early as 2012 (Doyle et al., Carmignac et al.; PMIDs: 23023332, 23103230). Clinical phenotypes of SGS include craniosynostosis and craniofacial features, motor and cognitive delays, mild-moderate intellectual disability, hypotonia, musculoskeletal anomalies, and cardiovascular problems such as aortic aneurysm. Variants in SKI have been identified in at least 40 probands with SGS (GeneReviews, Greally, 2020). Seven variants (missense and in-frame indel) reported in 13 probands in 4 publications (PMID: 23023332, 23103230, 24357594, 4736733) are included in this curation. Additionally, there is evidence that variants affecting amino acid position p.Thr180 may lead to phenotypes including thoracic aortic aneurysm and a marfanoid body habitus without intellectual disability, a feature which is often characteristic of SGS (PMID: 31980905). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is proposed to be dominant-negative (PMID: 23023332). Variants in SKI associated with SGS are concentrated in exon 1, a mutational hotspot, where variants exert a stabilizing effect on SKI protein function, attenuating the TGF-β signaling pathway (PMID: 33416497). This gene-disease association is also supported by experimental evidence including expression studies, animal models, and in vitro functional assays (PMID: 10906458, 23023332). In summary, SKI is definitively associated with Shprintzen-Goldberg syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This curation was approved by the ClinGen Craniofacial Malformations Gene Curation Expert Panel on 10/29/20 (SOP Version 8). The evidence summary was updated by the Heritable Thoracic Aortic Aneurysm and Dissection subgroup of the Hereditary Cardiovascular Disease Gene Curation Expert Panel on 7/23/2024.

Clinical Genomic Database (CGD)

Shprintzen-Goldberg craniosynostosis syndromeAD

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: Individuals have been described with a number of cardiovascular anomalies, including aortic root dilatation, and spontaneous rupture of arterial aneurysms, and surveillance (eg, including echocardiogram) may allow early management, decreasing morbidity and mortality

Refs: 23023332Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SKI variants in ClinVar

15 Conditions Cataloged
Shprintzen-Goldberg syndromeTotal: 931
Familial thoracic aortic aneurysm and aortic dissectionTotal: 768
not providedTotal: 383
not specifiedTotal: 157
SKI-related disorderTotal: 67
Intellectual disabilityTotal: 5
Neurodevelopmental disorderTotal: 3
Inborn genetic diseasesTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003036.4. 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.

EffectPLPVUSLBBSum
synonymous
4
clinvar
534
clinvar
4
clinvar
 542
missense
13
clinvar
17
clinvar
604
clinvar
111
clinvar
2
clinvar
 747
nonsense
11
clinvar
 11
start loss
1
clinvar
 1
frameshift
1
clinvar
2
clinvar
21
clinvar
 24
splice donor/acceptor (+/-2bp)
1
clinvar
4
clinvar
 5
Total142064564561330

Highest pathogenic variant AF is 0.0000031012444

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_003036.4RefSeqNP_003027.17MANE Select
ENST00000378536.5EnsemblENSP00000367797.47MANE Select
ENST00000851187.1EnsemblENSP00000521247.17Standard
ENST00000851187.2EnsemblENSP00000521247.17Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
skiaDanio rerio

Structure: bulbus arteriosus

Quality: amorphous

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • TGF-Ncore
  • Olfactory bulb development and olfactory learning
  • TGF-beta Signaling Pathway
  • TGF-beta Receptor Signaling
  • Signal Transduction

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • neural tube closure
  • lens morphogenesis in camera-type eye
  • transcription, DNA-templated
  • transforming growth factor beta receptor signaling pathway

Molecular Function

  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • transcription corepressor activity
  • protein binding
  • zinc ion binding
  • protein kinase binding

Cellular Component

  • nucleus
  • nucleoplasm
  • transcription factor complex
  • cytoplasm
  • centrosome

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000378536
Coding exons
7
Length
81425
Individuals with no LoFs
125412
Homozygous LoFs
0
Heterozygous LoFs
3
Defined
125415
p
0.0000120
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.513494380.7960.00002884563
Missense (PolyPhen)93185.760.500651946
Synonymous-4.873002101.430.00001471536
Loss of Function4.40124.50.04090.00000123293

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish0.000100.00010rare
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000180.000018rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: May play a role in terminal differentiation of skeletal muscle cells but not in the determination of cells to the myogenic lineage. Functions as a repressor of TGF-beta signaling. {ECO:0000269|PubMed:19049980}.;
Disease
DISEASE: Shprintzen-Goldberg craniosynostosis syndrome (SGS) [MIM:182212]: A very rare syndrome characterized by a marfanoid habitus, craniosynostosis, characteristic dysmorphic facial features, skeletal and cardiovascular abnormalities, mental retardation, developmental delay and learning disabilities. {ECO:0000269|PubMed:23023332, ECO:0000269|PubMed:23103230, ECO:0000269|PubMed:24357594, ECO:0000269|PubMed:24736733}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.152

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
K
Indispensability pred.
E
Indispensability score
1.00

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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