Human Gene Module / Chromosome 3 / TBC1D23

TBC1D23TBC1 domain family member 23

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
2 / 6
Rare Variants / Common Variants
11 / 0
Aliases
TBC1D23, NS4ATP1,  PCH11
Associated Syndromes
-
Chromosome Band
3q12.1-q12.2
Associated Disorders
DD/NDD, ID, EPS, ASD
Relevance to Autism

Homozygous mutations in the TBC1D23 gene were shown to be responsible for pontocerebellar hypoplasia type 11 (PCH11; OMIM 617695), an autosomal recessive neurodevelopmental disorder characterized by severely delayed psychomotor development with intellectual disability and poor speech, microcephaly, dysmorphic features, and hypoplasia of the pons and cerebellum on brain imaging (Marin-Valencia et al., 2017; Ivanova et al., 2017). All six affected individuals described in Marin-Valencia et al., 2017 presented with delayed or absent social development. Ivanova et al., 2017 reported that four of the seven affected individuals in their study presented with stereotypic movements (two of whom also presented with autistic behavior), in addition to two individuals that presented with poor communication and interaction and persistent repetitive motor behavior.

Molecular Function

Putative Rab GTPase-activating protein which plays a role in vesicular trafficking. Involved in endosome-to-Golgi trafficking. Acts as a bridging protein by binding simultaneously to golgins, including GOLGA1 and GOLGA4, located at the trans-Golgi, and to the WASH complex, located on endosome-derived vesicles. Plays a role in brain development, including in cortical neuron positioning. May also be important for neurite outgrowth, possibly through its involvement in membrane trafficking and cargo delivery, 2 processes that are essential for axonal and dendritic growth.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TBC1D23 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Homozygous Mutations in TBC1D23 Lead to a Non-degenerative Form of Pontocerebellar Hypoplasia Marin-Valencia I , et al. (2017) No DD, epilepsy/seizures
2 Support Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia and Alter Cortical Development Ivanova EL , et al. (2017) No ID, stereotypic movements, autistic behavior
3 Support - Mitani T et al. (2021) No -
4 Support - Zhou X et al. (2022) Yes -
5 Support - Cirnigliaro M et al. (2023) Yes -
6 Support - Mohammad-Reza Ghasemi et al. (2024) No Autistic features
Rare Variants   (11)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.876+1G>C - splice_site_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1029C>A p.Cys343Ter stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.1687+2T>G - splice_site_variant Familial Both parents Multiplex 28823707 Ivanova EL , et al. (2017)
c.726-2A>G - splice_site_variant Familial Both parents Simplex 28823706 Marin-Valencia I , et al. (2017)
c.1687+1G>A - splice_site_variant Familial Both parents Simplex 28823706 Marin-Valencia I , et al. (2017)
c.1687+2T>A - splice_site_variant Familial Both parents Multiplex 28823706 Marin-Valencia I , et al. (2017)
c.1553G>A p.Arg518Gln missense_variant Familial Both parents Multiplex 28823706 Marin-Valencia I , et al. (2017)
c.743_744del p.Gln248ArgfsTer43 frameshift_variant Familial Both parents Simplex 34582790 Mitani T et al. (2021)
c.458T>C p.Met153Thr missense_variant Familial Both parents Simplex 38347586 Mohammad-Reza Ghasemi et al. (2024)
c.1475_1476del p.Val492GlyfsTer8 frameshift_variant Familial Both parents Multiplex 28823707 Ivanova EL , et al. (2017)
c.1526delinsAA p.Ile509LysfsTer31 frameshift_variant Familial Both parents Multiplex 28823707 Ivanova EL , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Homozygous mutations in the TBC1D23 gene were shown to be responsible for pontocerebellar hypoplasia type 11 (PCH11; OMIM 617695), an autosomal recessive neurodevelopmental disorder characterized by severely delayed psychomotor development with intellectual disability and poor speech, microcephaly, dysmorphic features, and hypoplasia of the pons and cerebellum on brain imaging (Marin-Valencia et al., 2017; Ivanova et al., 2017). All six affected individuals described in Marin-Valencia et al., 2017 presented with delayed or absent social development. Ivanova et al., 2017 reported that four of the seven affected individuals in their study presented with stereotypic movements (two of whom also presented with autistic behavior), in addition to two individuals that presented with poor communication and interaction and persistent repetitive motor behavior.

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
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."

10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Homozygous mutations in the TBC1D23 gene were shown to be responsible for pontocerebellar hypoplasia type 11 (PCH11; OMIM 617695), an autosomal recessive neurodevelopmental disorder characterized by severely delayed psychomotor development with intellectual disability and poor speech, microcephaly, dysmorphic features, and hypoplasia of the pons and cerebellum on brain imaging (Marin-Valencia et al., 2017; Ivanova et al., 2017). All six affected individuals described in Marin-Valencia et al., 2017 presented with delayed or absent social development. Ivanova et al., 2017 reported that four of the seven affected individuals in their study presented with stereotypic movements (two of whom also presented with autistic behavior), in addition to two individuals that presented with poor communication and interaction and persistent repetitive motor behavior.

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.36020278795216

Ranking 24164/25841 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 0.0001115115687996

Ranking 13019/18225 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 0.40701662183728

Ranking 288/18665 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 0.37581698422579

Ranking 1722/20870 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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