Human Gene Module / Chromosome 22 / TNRC6B

TNRC6BTrinucleotide repeat containing 6B

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
13 / 19
Rare Variants / Common Variants
57 / 0
Aliases
TNRC6B, RP5-1042K10.7
Associated Syndromes
-
Chromosome Band
22q13.1
Associated Disorders
ADHD, ASD
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.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TNRC6B (19 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
10 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
11 Support - Alonso-Gonzalez A et al. (2021) Yes -
12 Support - Mitani T et al. (2021) No Epilepsy/seizures
13 Support - Mahjani B et al. (2021) Yes -
14 Support - Woodbury-Smith M et al. (2022) Yes -
15 Support - Cheng S et al. (2022) No -
16 Support - Zhou X et al. (2022) Yes -
17 Support - Hu C et al. (2023) Yes -
18 Support - Ashraf Yahia et al. (2024) No -
19 Support - Qi Yang et al. (2024) No ADHD, ID
Rare Variants   (57)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.566-3575G>T - intron_variant De novo - - 35982159 Zhou X et al. (2022)
c.566-3217G>A - missense_variant De novo - - 33004838 Wang T et al. (2020)
c.1170+1G>A - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.2539C>T p.Pro847Ser stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.565+3124del - frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.565+3237del - frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.4015C>T p.His1339Tyr stop_gained Unknown - - 33004838 Wang T et al. (2020)
- - copy_number_loss Familial Maternal - 32152250 Granadillo JL et al. (2020)
c.749G>T p.Trp250Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.750G>C p.Trp250Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.750G>T p.Trp250Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3835C>T p.Gln1279Ter stop_gained Unknown - - 34615535 Mahjani B et al. (2021)
c.1174G>T p.Gly392Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1183G>T p.Gly395Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2386C>T p.Arg796Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2522G>A p.Arg841His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1400G>A p.Gly467Glu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2735A>C p.Lys912Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.566-3311G>A - missense_variant Unknown - Simplex 33004838 Wang T et al. (2020)
c.4982G>C p.Gly1661Ala missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1879C>T p.Gln627Ter stop_gained De novo - Simplex 30564305 Guo H , et al. (2018)
c.3343C>T p.Arg1115Ter stop_gained De novo - - 27479843 Lelieveld SH et al. (2016)
c.565+3693del - frameshift_variant De novo - Simplex 38404251 Qi Yang et al. (2024)
c.566-3961_566-3960del - frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.2479C>T p.Gln827Ter stop_gained De novo - Simplex 25363768 Iossifov I et al. (2014)
- - copy_number_loss Unknown Not maternal Simplex 32152250 Granadillo JL et al. (2020)
c.2722A>T p.Asn908Tyr missense_variant Familial Paternal - 37007974 Hu C et al. (2023)
c.229G>A p.Glu77Lys missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.335C>T p.Pro112Leu missense_variant De novo - Simplex 38404251 Qi Yang et al. (2024)
c.648C>G p.Thr216%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.46-2A>G - splice_site_variant Familial Paternal Simplex 30504930 Guo H , et al. (2018)
c.933G>A p.Trp311Ter stop_gained De novo - Simplex 32152250 Granadillo JL et al. (2020)
c.1021+5G>C - splice_site_variant De novo - Simplex 32152250 Granadillo JL et al. (2020)
c.4980del p.Asp1660GlufsTer5 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.2039G>A p.Trp680Ter stop_gained De novo - Unknown 32152250 Granadillo JL et al. (2020)
c.3785C>T p.Ser1262Phe missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.3967C>T p.Gln1323Ter stop_gained De novo - Simplex 32152250 Granadillo JL et al. (2020)
c.3343C>T p.Arg1115Trp stop_gained Unknown - Unknown 32152250 Granadillo JL et al. (2020)
c.2320G>A p.Glu774Lys missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.566-3251_566-3250del - frameshift_variant Unknown - - 32152250 Granadillo JL et al. (2020)
c.3964C>T p.Gln1322Ter stop_gained Familial Paternal - 32152250 Granadillo JL et al. (2020)
c.4070T>A p.Val1357Glu missense_variant De novo - Unknown 32152250 Granadillo JL et al. (2020)
c.3799_3800del p.Ala1267HisfsTer130 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.2455dup p.Arg819LysfsTer18 frameshift_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.3316G>A p.Asp1106Asn missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.4612C>T p.Pro1538Ser missense_variant Familial Maternal Simplex 33004838 Wang T et al. (2020)
c.153_154insTTTGGAA p.Lys52PhefsTer10 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.566-3903_566-3902del - frameshift_variant De novo - Simplex 32152250 Granadillo JL et al. (2020)
c.2819G>T p.Ser940Ile missense_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.565+2806_565+2811delinsGGGGGGG - frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.566-3084T>C - splice_site_variant Familial Maternal Multiplex 32152250 Granadillo JL et al. (2020)
c.1352_1355del p.Lys451ArgfsTer51 frameshift_variant De novo - Simplex 25284784 Dong S , et al. (2014)
c.3943C>T p.Arg1315Ter stop_gained Unknown Not maternal Simplex 32152250 Granadillo JL et al. (2020)
c.2138G>C p.Arg713Pro missense_variant Familial Both parents Multiplex 34582790 Mitani T et al. (2021)
c.830_836del p.Asn277MetfsTer3 frameshift_variant De novo - Simplex 38300321 Ashraf Yahia et al. (2024)
c.830_836del p.Asn277MetfsTer3 frameshift_variant De novo - Simplex 32152250 Granadillo JL et al. (2020)
c.3148_3151del p.Asn1050SerfsTer8 frameshift_variant De novo - 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

criteria met
See SFARI Gene'scoring criteria
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.

1/1/2021
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.

Reports Added
[Exploring the biological role of postzygotic and germinal de novo mutations in ASD2021]
10/1/2020
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.

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
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.

Reports Added
[Pathogenic variants in TNRC6B cause a genetic disorder characterised by developmental delay/intellectual disability and a spectrum of neurobehavioural phenotypes including autism and ADHD2020]
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.

Reports Added
[Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.2015]
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.

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
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.

Reports Added
[Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.2018]
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.

Reports Added
[Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.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).

Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016]
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).

Reports Added
[De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
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.
Original Source
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
Original Source
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
Original Source
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).
Original Source
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.
Original Source
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.
Original Source
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