Human Gene Module / Chromosome 22 / TNRC6B

TNRC6BTrinucleotide repeat containing 6B

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
7 / 9
Rare Variants / Common Variants
23 / 0
Aliases
TNRC6B, RP5-1042K10.7
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
22q13.1
Associated Disorders
ASD, ADHD
Relevance to Autism

Two de novo loss-of-function variants in the TNRC6B gene have been identified in ASD probands from the Simons Simplex Collection (refs).

Molecular Function

Plays a role in RNA-mediated gene silencing by both micro-RNAs (miRNAs) and short interfering RNAs (siRNAs). Required for miRNA-dependent translational repression and siRNA-dependent endonucleolytic cleavage of complementary mRNAs by argonaute family proteins.

Reports related to TNRC6B (9 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder. Dong S , et al. (2014) Yes -
2 Recent Recommendation The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
4 Support Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci. Sanders SJ , et al. (2015) Yes -
5 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
6 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) Yes -
7 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes. Guo H , et al. (2018) Yes -
8 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model. Guo H , et al. (2018) Yes -
9 Recent Recommendation Pathogenic variants in TNRC6B cause a genetic disorder characterised by developmental delay/intellectual disability and a spectrum of neurobehavioural phenotypes including autism and ADHD Granadillo JL et al. (2020) No ASD, ADHD
Rare Variants   (23)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Familial Maternal - 32152250 Granadillo JL et al. (2020)
c.1879C>T p.Gln627Ter stop_gained De novo NA Simplex 30564305 Guo H , et al. (2018)
c.3343C>T p.Arg1115Ter stop_gained De novo NA - 27479843 Lelieveld SH et al. (2016)
- - copy_number_loss Unknown Not maternal Simplex 32152250 Granadillo JL et al. (2020)
c.46-2A>G - splice_site_variant Familial Paternal Simplex 30504930 Guo H , et al. (2018)
c.2479C>T p.Gln827Ter stop_gained De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.933G>A p.Trp311Ter stop_gained De novo NA Simplex 32152250 Granadillo JL et al. (2020)
c.3343C>T p.Arg1115Trp stop_gained Unknown - Unknown 32152250 Granadillo JL et al. (2020)
c.1021+5G>C - splice_site_variant De novo NA Simplex 32152250 Granadillo JL et al. (2020)
c.566-3251_566-3250del - frameshift_variant Unknown - - 32152250 Granadillo JL et al. (2020)
c.2039G>A p.Trp680Ter stop_gained De novo NA Unknown 32152250 Granadillo JL et al. (2020)
c.3964C>T p.Gln1322Ter stop_gained Familial Paternal - 32152250 Granadillo JL et al. (2020)
c.3967C>T p.Gln1323Ter stop_gained De novo NA Simplex 32152250 Granadillo JL et al. (2020)
c.3316G>A p.Asp1106Asn missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.4070T>A p.Val1357Glu missense_variant De novo NA Unknown 32152250 Granadillo JL et al. (2020)
c.2455dup p.Arg819LysfsTer18 frameshift_variant De novo NA Simplex 30564305 Guo H , et al. (2018)
c.566-3903_566-3902del - frameshift_variant De novo NA Simplex 32152250 Granadillo JL et al. (2020)
c.566-3084T>C - splice_site_variant Familial Maternal Multiplex 32152250 Granadillo JL et al. (2020)
c.565+2806_565+2811delinsGGGGGGG - frameshift_variant De novo NA - 28191889 Stessman HA , et al. (2017)
c.3943C>T p.Arg1315Ter stop_gained Unknown Not maternal Simplex 32152250 Granadillo JL et al. (2020)
c.1352_1355del p.Lys451ArgfsTer51 frameshift_variant De novo NA Simplex 25284784 Dong S , et al. (2014)
c.830_836del p.Asn277MetfsTer3 frameshift_variant De novo NA Simplex 32152250 Granadillo JL et al. (2020)
c.3148_3151del p.Asn1050SerfsTer8 frameshift_variant De novo NA Unknown 32152250 Granadillo JL et al. (2020)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo LoF variants in the TNRC6B gene (one frameshift, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 25284784, 25363768). A third de novo LoF variant was identified in an ASD proband from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017.

Score Delta: Score remained at 2

2

Strong Candidate

See all Category 2 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.

4/1/2020
2
icon
2

Score remained at 2

Description

Two de novo LoF variants in the TNRC6B gene (one frameshift, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 25284784, 25363768). A third de novo LoF variant was identified in an ASD proband from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017.

1/1/2020
2
icon
2

Score remained at 2

Description

Two de novo LoF variants in the TNRC6B gene (one frameshift, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 25284784, 25363768). A third de novo LoF variant was identified in an ASD proband from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017.

10/1/2019
2
icon
2

Score remained at 2

New Scoring Scheme
Description

Two de novo LoF variants in the TNRC6B gene (one frameshift, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 25284784, 25363768). A third de novo LoF variant was identified in an ASD proband from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017.

Reports Added
[New Scoring Scheme]
1/1/2019
2
icon
2

Score remained at 2

Description

Two de novo LoF variants in the TNRC6B gene (one frameshift, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 25284784, 25363768). A third de novo LoF variant was identified in an ASD proband from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017.

10/1/2018
2
icon
2

Score remained at 2

Description

Two de novo LoF variants in the TNRC6B gene (one frameshift, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 25284784, 25363768). A third de novo LoF variant was identified in an ASD proband from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017.

1/1/2017
3
icon
2

Decreased from 3 to 2

Description

Two de novo LoF variants in the TNRC6B gene (one frameshift, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 25284784, 25363768). A third de novo LoF variant was identified in an ASD proband from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017.

7/1/2016
3
icon
3

Decreased from 3 to 3

Description

Two de novo LoF variants in the TNRC6B gene (one frameshift, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 25284784, 25363768).

1/1/2016
3
icon
3

Decreased from 3 to 3

Description

Two de novo LoF variants in the TNRC6B gene (one frameshift, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 25284784, 25363768).

10/1/2014
icon
3

Increased from to 3

Description

Two de novo LoF variants in the TNRC6B gene (one frameshift, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 25284784, 25363768).

Krishnan Probability Score

Score 0.57806937492719

Ranking 616/25841 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.
ExAC Score

Score 0.99999980275071

Ranking 219/18225 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
Iossifov Probability Score

Score 0.965

Ranking 64/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.003223538101791

Ranking 23/18665 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).
Larsen Cumulative Evidence Score

Score 12

Ranking 165/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.44264869484635

Ranking 992/20870 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.
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SFARI Gene Update

We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
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