Human Gene Module / Chromosome 4 / TBCK

TBCKTBC1 domain containing kinase

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
1 / 5
Rare Variants / Common Variants
18 / 0
EAGLE Score
1
Limited Learn More
Aliases
TBCK, HSPC302,  IHPRF3L, TBCK
Associated Syndromes
-
Chromosome Band
4q24
Associated Disorders
DD/NDD, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic
Relevance to Autism

Infantile hypotonia with psychomotor retardation and characteristic facies-3 (OMIM 616900) is a severe autosomal recessive neurodevelopmental disorder caused by biallelic variants in the TBCK gene. Bhoj et al., 2016 reported 13 individuals from nine unrelated families with likely pathogenic biallelic variants in the TBCK gene; autism was observed in one of these individuals.

Molecular Function

This gene encodes a protein that contains a protein kinase domain, a Rhodanase-like domain and the Tre-2/Bub2/Cdc16 (TBC) domain. The encoded protein is thought to play a role in actin organization, cell growth and cell proliferation by regulating the mammalian target of the rapamycin (mTOR) signaling pathway. This protein may also be involved in the transcriptional regulation of the components of the mTOR complex.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TBCK (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Mutations in TBCK, Encoding TBC1-Domain-Containing Kinase, Lead to a Recognizable Syndrome of Intellectual Disability and Hypotonia Bhoj EJ , et al. (2016) No ASD
2 Support - Miyamoto S et al. (2021) No DD
3 Support - Zhou X et al. (2022) Yes -
4 Support - Amerh S Alqahtani et al. (2023) No -
5 Support - Purvi Majethia et al. (2024) No DD, ID
Rare Variants   (18)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2195A>G p.Tyr732Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.790C>G p.Pro264Ala missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.376C>T p.Arg126Ter stop_gained Familial - Multiplex 27040691 Bhoj EJ , et al. (2016)
c.1039C>G p.Arg347Gly missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1201T>C p.Tyr401His missense_variant Familial Maternal - 33958710 Miyamoto S et al. (2021)
c.1588C>T p.Arg530Cys missense_variant Familial Paternal - 33958710 Miyamoto S et al. (2021)
c.783-103_783-100del - frameshift_variant Familial - Multiplex 27040691 Bhoj EJ , et al. (2016)
c.455+4C>G - splice_site_variant Familial Both parents Simplex 27040691 Bhoj EJ , et al. (2016)
c.1934A>G p.Asp645Gly splice_site_variant Familial - Multiplex 27040691 Bhoj EJ , et al. (2016)
c.376C>T p.Arg126Ter stop_gained Familial Both parents Simplex 27040691 Bhoj EJ , et al. (2016)
c.557A>G p.Asp186Gly missense_variant Familial - Multiplex 38374498 Purvi Majethia et al. (2024)
c.1652T>C p.Leu551Pro missense_variant Familial Both parents Simplex 27040691 Bhoj EJ , et al. (2016)
c.783-75_783-74insAT - frameshift_variant Familial Both parents Simplex 27040691 Bhoj EJ , et al. (2016)
c.1860+2T>A - splice_site_variant Familial Both parents Unknown 37799141 Amerh S Alqahtani et al. (2023)
c.1774G>A p.Glu592Lys splice_site_variant Familial Both parents Multiplex 27040691 Bhoj EJ , et al. (2016)
c.737_738del p.Val246AspfsTer6 frameshift_variant Familial - Multiplex 38374498 Purvi Majethia et al. (2024)
c.(658+1_659-1)_(2059+1_2060-1)del p.(=) copy_number_loss Familial - Multiplex 27040691 Bhoj EJ , et al. (2016)
c.1246del p.Ser416AlafsTer13 frameshift_variant Familial Both parents Multiplex 27040691 Bhoj EJ , et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2021
1
icon
1

Score remained at 1

Description

Infantile hypotonia with psychomotor retardation and characteristic facies-3 (OMIM 616900) is a severe autosomal recessive neurodevelopmental disorder caused by biallelic variants in the TBCK gene. Bhoj et al., 2016 reported 13 individuals from nine unrelated families with likely pathogenic biallelic variants in the TBCK gene; autism was observed in one of these individuals.

Reports Added
[Comprehensive genetic analysis confers high diagnostic yield in 16 Japanese patients with corpus callosum anomalies2021]
10/1/2019
icon
1

Increased from to 1

New Scoring Scheme
Description

Infantile hypotonia with psychomotor retardation and characteristic facies-3 (OMIM 616900) is a severe autosomal recessive neurodevelopmental disorder caused by biallelic variants in the TBCK gene. Bhoj et al., 2016 reported 13 individuals from nine unrelated families with likely pathogenic biallelic variants in the TBCK gene; autism was observed in one of these individuals.

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.44191298923826

Ranking 18039/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 3.2154815637914E-6

Ranking 14646/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.68665681226976

Ranking 1077/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.557453100351

Ranking 218/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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