Human Gene Module / Chromosome 19 / NACC1

NACC1nucleus accumbens associated 1

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
5 / 12
Rare Variants / Common Variants
11 / 0
Aliases
NACC1, BEND8,  BTBD14B,  BTBD30,  NAC-1,  NAC1
Associated Syndromes
-
Chromosome Band
19p13.13
Associated Disorders
SCZ, DD/NDD, ASD
Relevance to Autism

A recurrent de novo heterozygous missense variant in the NACC1 gene (c.892C>T;p.Arg298Trp) was osberved in seven individuals presenting with a neurodevelopmental disorder characterized by microcephaly, profound developmental delay and/or intellectual disability, cataracts, epilepsy, irritability, failure to thrive, and stereotypic hand movements (Schoch et al., 2017). De novo mutations in NACC1 had previously been observed in Gilissen et al., 2014 (a de novo missense variant in a patient originally described in de Ligt et al., 2012 that presented with developmental delay, intellectual disability, autistic features, and schizoaffective disorder) and in Iossifov et al., 2014 (a de novo splice-site variant in an ASD proband from the Simons Simplex Collection).

Molecular Function

This gene encodes a member of the BTB/POZ protein family. BTB/POZ proteins are involved in several cellular processes including proliferation, apoptosis and transcription regulation. The encoded protein is a transcriptional repressor that plays a role in stem cell self-renewal and pluripotency maintenance.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to NACC1 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Genome sequencing identifies major causes of severe intellectual disability Gilissen C , et al. (2014) No Autistic features, schizoaffective disorder
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Primary A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay Schoch K , et al. (2017) No Stereotypic hand movements, microcephaly
4 Support Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly Boonsawat P , et al. (2019) No DD, stereotypies
5 Support Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants Lecoquierre F , et al. (2019) No -
6 Support Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing Bruel AL , et al. (2019) No -
7 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
8 Support - Mahjani B et al. (2021) Yes -
9 Support - Zhou X et al. (2022) Yes -
10 Support - Karthika Ajit Valaparambil et al. () Yes -
11 Support - Mark A Deehan et al. (2024) No -
12 Support - Chengyan Li et al. (2024) No Stereotypy
Rare Variants   (11)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1120G>C p.Gly374Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.254G>A p.Cys85Tyr missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.892C>T p.Arg298Trp missense_variant De novo - - 28132692 Schoch K , et al. (2017)
c.892C>T p.Arg298Trp missense_variant De novo - - 31231135 Bruel AL , et al. (2019)
c.946+2T>C - splice_site_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1402C>T p.Arg468Cys missense_variant De novo - - 24896178 Gilissen C , et al. (2014)
c.1324+27C>T - intron_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.892C>T p.Arg298Trp missense_variant De novo - - 31036916 Lecoquierre F , et al. (2019)
c.892C>T p.Arg298Trp missense_variant De novo - Simplex 39528574 Chengyan Li et al. (2024)
c.892C>T p.Arg298Trp missense_variant De novo - Simplex 30842647 Boonsawat P , et al. (2019)
c.1354A>G p.Lys452Glu missense_variant Unknown - - 37943464 Karthika Ajit Valaparambil et al. ()
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."

4/1/2022
3S
icon
1

Decreased from 3S to 1

1/1/2020
3S
icon
3S

Decreased from 3S to 3S

Description

A recurrent de novo heterozygous missense variant in the NACC1 gene (c.892C>T;p.Arg298Trp) was observed in seven individuals presenting with a neurodevelopmental disorder characterized by microcephaly, profound developmental delay and/or intellectual disability, cataracts, epilepsy, irritability, failure to thrive, and stereotypic hand movements (Schoch et al., 2017). De novo mutations in NACC1 had previously been observed in Gilissen et al., 2014 (a de novo missense variant in a patient originally described in de Ligt et al., 2012 that presented with developmental delay, intellectual disability, autistic features, and schizoaffective disorder) and in Iossifov et al., 2014 (a de novo splice-site variant in an ASD proband from the Simons Simplex Collection).

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

A recurrent de novo heterozygous missense variant in the NACC1 gene (c.892C>T;p.Arg298Trp) was observed in seven individuals presenting with a neurodevelopmental disorder characterized by microcephaly, profound developmental delay and/or intellectual disability, cataracts, epilepsy, irritability, failure to thrive, and stereotypic hand movements (Schoch et al., 2017). De novo mutations in NACC1 had previously been observed in Gilissen et al., 2014 (a de novo missense variant in a patient originally described in de Ligt et al., 2012 that presented with developmental delay, intellectual disability, autistic features, and schizoaffective disorder) and in Iossifov et al., 2014 (a de novo splice-site variant in an ASD proband from the Simons Simplex Collection).

Reports Added
[New Scoring Scheme]
7/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

A recurrent de novo heterozygous missense variant in the NACC1 gene (c.892C>T;p.Arg298Trp) was observed in seven individuals presenting with a neurodevelopmental disorder characterized by microcephaly, profound developmental delay and/or intellectual disability, cataracts, epilepsy, irritability, failure to thrive, and stereotypic hand movements (Schoch et al., 2017). De novo mutations in NACC1 had previously been observed in Gilissen et al., 2014 (a de novo missense variant in a patient originally described in de Ligt et al., 2012 that presented with developmental delay, intellectual disability, autistic features, and schizoaffective disorder) and in Iossifov et al., 2014 (a de novo splice-site variant in an ASD proband from the Simons Simplex Collection).

Reports Added
[Variantrecurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense v...2019] [Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing.2019]
4/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

A recurrent de novo heterozygous missense variant in the NACC1 gene (c.892C>T;p.Arg298Trp) was observed in seven individuals presenting with a neurodevelopmental disorder characterized by microcephaly, profound developmental delay and/or intellectual disability, cataracts, epilepsy, irritability, failure to thrive, and stereotypic hand movements (Schoch et al., 2017). De novo mutations in NACC1 had previously been observed in Gilissen et al., 2014 (a de novo missense variant in a patient originally described in de Ligt et al., 2012 that presented with developmental delay, intellectual disability, autistic features, and schizoaffective disorder) and in Iossifov et al., 2014 (a de novo splice-site variant in an ASD proband from the Simons Simplex Collection).

Reports Added
[Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly.2019]
1/1/2017
icon
4S

Increased from to 4S

Description

A recurrent de novo heterozygous missense variant in the NACC1 gene (c.892C>T;p.Arg298Trp) was observed in seven individuals presenting with a neurodevelopmental disorder characterized by microcephaly, profound developmental delay and/or intellectual disability, cataracts, epilepsy, irritability, failure to thrive, and stereotypic hand movements (Schoch et al., 2017). De novo mutations in NACC1 had previously been observed in Gilissen et al., 2014 (a de novo missense variant in a patient originally described in de Ligt et al., 2012 that presented with developmental delay, intellectual disability, autistic features, and schizoaffective disorder) and in Iossifov et al., 2014 (a de novo splice-site variant in an ASD proband from the Simons Simplex Collection).

Krishnan Probability Score

Score 0.41670887955315

Ranking 21320/25841 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 0.96494693620972

Ranking 2454/18225 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 0.932

Ranking 108/239 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 0.46845367805031

Ranking 385/18665 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 0.25555748671949

Ranking 3398/20870 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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