Human Gene Module / Chromosome 17 / NCOR1

NCOR1nuclear receptor corepressor 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
9 / 12
Rare Variants / Common Variants
51 / 0
Aliases
NCOR1, N-CoR,  N-CoR1,  PPP1R109,  TRAC1,  hN-CoR
Associated Syndromes
-
Chromosome Band
17p12-p11.2
Associated Disorders
ASD
Relevance to Autism

A de novo potentially damaging missense variant in the NCOR1 gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2012); a de novo splice-site variant and paternally-inherited potentially damaging missense variant in this gene were identified in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). Interaction of the NCoR/SMRT co-repressor with MECP2 is abolished by mutations associated with Rett syndrome (Lyst et al., 2013).

Molecular Function

This gene encodes a protien that mediates transcriptional repression by certain nuclear receptors and is part of a complex which promotes histone deacetylation and the formation of repressive chromatin structures which may impede the access of basal transcription factors.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Fruit fly
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to NCOR1 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo gene disruptions in children on the autistic spectrum Iossifov I , et al. (2012) Yes -
2 Support Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor Lyst MJ , et al. (2013) No -
3 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
4 Support Haploinsufficiency of NCOR1 associated with autism spectrum disorder, scoliosis, and abnormal palatogenesis Sakaguchi Y , et al. (2018) Yes -
5 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
6 Recent Recommendation Loss of function of NCOR1 and NCOR2 impairs memory through a novel GABAergic hypothalamus-CA3 projection Zhou W , et al. (2019) No ASD
7 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
8 Support - Li D et al. (2022) Yes -
9 Support - Zhou X et al. (2022) Yes -
10 Support - Wang J et al. (2023) Yes -
11 Support - Sheth F et al. (2023) Yes DD, ID
12 Support - Erica Rosina et al. (2024) No -
Rare Variants   (51)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 30664766 Zhou W , et al. (2019)
c.3449-1G>C - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.436-8C>A - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.1855+2T>G - splice_site_variant De novo - - 30664766 Zhou W , et al. (2019)
c.2899-1G>A p.? splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.7387+2T>G p.? splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.3449-1G>C p.? splice_site_variant De novo - - 27824329 Wang T , et al. (2016)
c.6761A>G p.His2254Arg missense_variant Unknown - - 34968013 Li D et al. (2022)
c.340G>C p.Val114Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.361C>T p.Arg121Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.644A>T p.Lys215Ile missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.667G>C p.Val223Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.749C>T p.Ala250Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1855+1G>T - splice_site_variant De novo - - 30289594 Sakaguchi Y , et al. (2018)
c.4492C>T p.Arg1498Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3243G>A p.Pro1081%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.5020C>T p.Pro1674Ser stop_gained Unknown - Simplex 33004838 Wang T et al. (2020)
c.3699A>G p.Gly1233%3D splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.6897A>G p.Ala2299%3D splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.229C>G p.Pro77Ala missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.395C>T p.Pro132Leu missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1805C>T p.Ala602Val missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.5235del p.Ile1745MetfsTer33 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.3122C>T p.Pro1025Leu missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.1705C>T p.Pro569Ser missense_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.2876G>A XP_005256923.1:p.Arg959Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3526C>T XP_005256923.1:p.Arg1176Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3688C>T XP_005256923.1:p.Arg1230Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3899G>A XP_005256923.1:p.Ser1300Asn missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4021G>A XP_005256923.1:p.Gly1341Arg missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4495C>T XP_005256923.1:p.Arg1499Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4586G>A XP_005256923.1:p.Arg1529His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4592G>A XP_005256923.1:p.Arg1531Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5135G>A XP_005256923.1:p.Arg1712His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5467C>T XP_005256923.1:p.Arg1823Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5492G>A XP_005256923.1:p.Arg1831Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6182G>T XP_005256923.1:p.Ser2061Ile missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6391C>T XP_005256923.1:p.Arg2131Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6550C>T XP_005256923.1:p.Arg2184Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6799C>T XP_005256923.1:p.Arg2267Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6800G>A XP_005256923.1:p.Arg2267His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6806C>T XP_005256923.1:p.Pro2269Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6892C>T XP_005256923.1:p.Arg2298Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6893G>A XP_005256923.1:p.Arg2298His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6897G>C XP_005256923.1:p.Lys2299Asn missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6923C>T XP_005256923.1:p.Ser2308Phe missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.7175G>A XP_005256923.1:p.Arg2392Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2930G>A p.Arg977Gln missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.5849G>A p.Arg1950His missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.5940C>A p.Ser1980Arg missense_variant Familial Paternal Simplex 37543562 Sheth F et al. (2023)
c.4243del p.Arg1415ValfsTer13 frameshift_variant Familial Maternal Simplex 38041506 Erica Rosina et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo potentially damaging missense variant in the NCOR1 gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2012); a de novo splice-site variant and paternally-inherited potentially damaging missense variant in this gene were identified in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). A second de novo splice-site variant in the NCOR1 gene was identified in a Japanese girl diagnosed with ASD in Sakaguchi et al., 2018. Interaction of the NCoR/SMRT co-repressor with MECP2 is abolished by mutations associated with Rett syndrome (Lyst et al., 2013). Zhou et al., 2019 demonstrated that mice with knock-in mutations in the deacetylase activation domains of NCOR1 and NCOR2 exhibited memory deficits, reduced anxiety levels, and reduced social interactions; in the same report, a de novo splice-site variant in the NCOR1 gene found in an 8-year-old boy with ASD, developmental delay, and epilepsy was retrieved from the Deciphering Developmental Disorders (DDD) website.

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.

10/1/2020
2
icon
2

Score remained at 2

Description

A de novo potentially damaging missense variant in the NCOR1 gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2012); a de novo splice-site variant and paternally-inherited potentially damaging missense variant in this gene were identified in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). A second de novo splice-site variant in the NCOR1 gene was identified in a Japanese girl diagnosed with ASD in Sakaguchi et al., 2018. Interaction of the NCoR/SMRT co-repressor with MECP2 is abolished by mutations associated with Rett syndrome (Lyst et al., 2013). Zhou et al., 2019 demonstrated that mice with knock-in mutations in the deacetylase activation domains of NCOR1 and NCOR2 exhibited memory deficits, reduced anxiety levels, and reduced social interactions; in the same report, a de novo splice-site variant in the NCOR1 gene found in an 8-year-old boy with ASD, developmental delay, and epilepsy was retrieved from the Deciphering Developmental Disorders (DDD) website.

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
10/1/2019
2
icon
2

Score remained at 2

New Scoring Scheme
Description

A de novo potentially damaging missense variant in the NCOR1 gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2012); a de novo splice-site variant and paternally-inherited potentially damaging missense variant in this gene were identified in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). A second de novo splice-site variant in the NCOR1 gene was identified in a Japanese girl diagnosed with ASD in Sakaguchi et al., 2018. Interaction of the NCoR/SMRT co-repressor with MECP2 is abolished by mutations associated with Rett syndrome (Lyst et al., 2013). Zhou et al., 2019 demonstrated that mice with knock-in mutations in the deacetylase activation domains of NCOR1 and NCOR2 exhibited memory deficits, reduced anxiety levels, and reduced social interactions; in the same report, a de novo splice-site variant in the NCOR1 gene found in an 8-year-old boy with ASD, developmental delay, and epilepsy was retrieved from the Deciphering Developmental Disorders (DDD) website.

Reports Added
[New Scoring Scheme]
1/1/2019
3
icon
2

Decreased from 3 to 2

Description

A de novo potentially damaging missense variant in the NCOR1 gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2012); a de novo splice-site variant and paternally-inherited potentially damaging missense variant in this gene were identified in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). A second de novo splice-site variant in the NCOR1 gene was identified in a Japanese girl diagnosed with ASD in Sakaguchi et al., 2018. Interaction of the NCoR/SMRT co-repressor with MECP2 is abolished by mutations associated with Rett syndrome (Lyst et al., 2013). Zhou et al., 2019 demonstrated that mice with knock-in mutations in the deacetylase activation domains of NCOR1 and NCOR2 exhibited memory deficits, reduced anxiety levels, and reduced social interactions; in the same report, a de novo splice-site variant in the NCOR1 gene found in an 8-year-old boy with ASD, developmental delay, and epilepsy was retrieved from the Deciphering Developmental Disorders (DDD) website.

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018] [Loss of function of NCOR1 and NCOR2 impairs memory through a novel GABAergic hypothalamus-CA3 projection.2019]
10/1/2018
4
icon
3

Decreased from 4 to 3

Description

A de novo potentially damaging missense variant in the NCOR1 gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2012); a de novo splice-site variant and paternally-inherited potentially damaging missense variant in this gene were identified in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). A second de novo splice-site variant in the NCOR1 gene was identified in a Japanese girl diagnosed with ASD in Sakaguchi et al., 2018. Interaction of the NCoR/SMRT co-repressor with MECP2 is abolished by mutations associated with Rett syndrome (Lyst et al., 2013).

Reports Added
[Haploinsufficiency of NCOR1 associated with autism spectrum disorder, scoliosis, and abnormal palatogenesis.2018]
10/1/2016
icon
4

Increased from to 4

Description

A de novo potentially damaging missense variant in the NCOR1 gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2012); a de novo splice-site variant and paternally-inherited potentially damaging missense variant in this gene were identified in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). Interaction of the NCoR/SMRT co-repressor with MECP2 is abolished by mutations associated with Rett syndrome (Lyst et al., 2013).

Krishnan Probability Score

Score 0.51230585606491

Ranking 1807/25841 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 0.99999999925682

Ranking 94/18225 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 0.876

Ranking 169/239 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 0.93565955885736

Ranking 12947/18665 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 0.4518079724158

Ranking 904/20870 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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