Human Gene Module / Chromosome 4 / NAA15

NAA15N(alpha)-acetyltransferase 15, NatA auxiliary subunit

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
7 / 13
Rare Variants / Common Variants
53 / 0
Aliases
NAA15, Ga19,  NARG1,  NAT1P,  NATH,  TBDN,  TBDN100
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
4q31.1
Associated Disorders
ADHD, ID, ASD, EPS
Relevance to Autism

A de novo loss-of-function (LoF) variant and a de novo missense variant that is predicted to be damaging were identified in the NAA15 gene in unrelated ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Furthermore, analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified NAA15 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene. Three novel de novo LoF variants in NAA15 were identified in probands reported to have a formal diagnosis of ASD in the Supplementary Material from Stessman et al., 2017 (PMID 28191889). An additional de novo LoF variant in NAA15 was identified in an ASD proband from a multiplex family by whole genome sequencing as part of the MSSNG initiative in Yuen et al., 2017 (PMID 28263302).

Molecular Function

Auxillary subunit of the N-terminal acetyltransferase A (NatA) complex which displays alpha (N-terminal) acetyltransferase activity. The NAT activity may be important for vascular, hematopoietic and neuronal growth and development.

Reports related to NAA15 (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
2 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
3 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
4 Recent Recommendation Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) Yes -
5 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
6 Support Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability. Zhao JJ , et al. (2017) No -
7 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder. Takata A , et al. (2018) Yes -
8 Support Phenotypic consequences of gene disruption by a balanced de novo translocation involving SLC6A1 and NAA15. Pesz K , et al. (2018) No -
9 Recent Recommendation Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies. Cheng H , et al. (2018) No ASD, ADHD, behavioral problems
10 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model. Guo H , et al. (2018) Yes -
11 Support Phenotypic and biochemical analysis of an international cohort of individuals with variants in NAA10 and NAA15. Cheng H , et al. (2019) No ID, epilepsy/seizures
12 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. Monies D , et al. (2019) No Macrocephaly
13 Support Autism-associated missense genetic variants impact locomotion and neurodevelopment in Caenorhabditis elegans. Wong WR , et al. (2019) Yes -
Rare Variants   (53)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo NA - 29621621 Pesz K , et al. (2018)
c.232A>T p.Lys78Ter stop_gained Unknown - - 29656860 Cheng H , et al. (2018)
c.908-2A>G - splice_site_variant De novo NA - 29656860 Cheng H , et al. (2018)
c.913A>T p.Lys305Ter stop_gained De novo NA - 29656860 Cheng H , et al. (2018)
c.1087+2T>C - splice_site_variant De novo NA - 29656860 Cheng H , et al. (2018)
c.1906G>T p.Gly636Ter stop_gained De novo NA - 29656860 Cheng H , et al. (2018)
c.868G>T p.Gly290Ter stop_gained Unknown - - 28191889 Stessman HA , et al. (2017)
c.2344C>T p.Arg782Ter stop_gained Unknown - - 28191889 Stessman HA , et al. (2017)
c.2392A>T p.Asn798Tyr stop_gained Unknown - - 28191889 Stessman HA , et al. (2017)
c.1540-1G>A - splice_site_variant De novo NA Simplex 30564305 Guo H , et al. (2018)
c.2086A>T p.Lys696Ter stop_gained De novo NA - 28191889 Stessman HA , et al. (2017)
c.1413A>C p.Glu471Asp missense_variant De novo NA - 31127942 Cheng H , et al. (2019)
c.1450T>C p.Cys484Arg missense_variant De novo NA - 31127942 Cheng H , et al. (2019)
c.248G>A p.Trp83Ter stop_gained De novo NA Simplex 29656860 Cheng H , et al. (2018)
c.1645C>T p.Arg549Ter stop_gained Unknown - Simplex 31130284 Monies D , et al. (2019)
c.334G>A p.Asp112Asn missense_variant Unknown - - 28191889 Stessman HA , et al. (2017)
c.74A>C p.Gln25Pro missense_variant De novo NA Simplex 30564305 Guo H , et al. (2018)
c.2303C>A p.Ala768Asp stop_gained De novo NA Simplex 29656860 Cheng H , et al. (2018)
c.2322C>G p.Tyr774Ter stop_gained De novo NA Simplex 29656860 Cheng H , et al. (2018)
c.1424C>T p.Ala475Val missense_variant Unknown - - 28191889 Stessman HA , et al. (2017)
c.309C>G p.Tyr103Ter stop_gained De novo NA Simplex 25363760 De Rubeis S , et al. (2014)
c.163del p.Thr55HisfsTer2 frameshift_variant De novo NA - 29656860 Cheng H , et al. (2018)
c.841G>C p.Glu281Gln missense_variant De novo NA Simplex 28990276 Zhao JJ , et al. (2017)
c.2441T>C p.Leu814Pro missense_variant De novo NA Simplex 31127942 Cheng H , et al. (2019)
c.287dup p.Tyr96Ter frameshift_variant De novo NA Simplex 29656860 Cheng H , et al. (2018)
c.420dup p.Leu141ThrfsTer25 frameshift_variant De novo NA - 29656860 Cheng H , et al. (2018)
c.1413A>C p.Glu471Asp missense_variant De novo NA Simplex 31130284 Monies D , et al. (2019)
c.1695T>A p.Tyr565Ter stop_gained De novo NA Multiplex 28191889 Stessman HA , et al. (2017)
c.1841del p.Asn614MetfsTer22 frameshift_variant De novo NA - 29656860 Cheng H , et al. (2018)
c.239_240del p.His80ArgfsTer17 frameshift_variant Unknown - - 29656860 Cheng H , et al. (2018)
c.1134C>A p.Tyr378Ter stop_gained Familial Paternal Simplex 29656860 Cheng H , et al. (2018)
c.1396T>C p.Ser466Pro missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2141G>A p.Arg714His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.228_232del p.Asp76GlufsTer20 frameshift_variant De novo NA - 29656860 Cheng H , et al. (2018)
c.239_240del p.His80ArgfsTer17 frameshift_variant De novo NA - 29656860 Cheng H , et al. (2018)
c.1795_1798del p.Gln599GlufsTer9 frameshift_variant Unknown - - 29656860 Cheng H , et al. (2018)
c.1348A>G p.Lys450Glu missense_variant Familial Paternal - 28191889 Stessman HA , et al. (2017)
c.1014G>T p.Lys338Asn missense_variant De novo NA Simplex 25363760 De Rubeis S , et al. (2014)
c.1144C>A p.Gln382Lys missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.1009_1012del p.Glu337ArgfsTer5 frameshift_variant De novo NA - 29656860 Cheng H , et al. (2018)
c.1798_1801del p.Arg600GlufsTer8 frameshift_variant De novo NA - 29656860 Cheng H , et al. (2018)
c.239_240del p.His80ArgfsTer17 frameshift_variant Unknown - - 28191889 Stessman HA , et al. (2017)
c.154A>T p.Lys52Ter stop_gained Unknown - Multi-generational 28191889 Stessman HA , et al. (2017)
c.264del p.Leu89PhefsTer19 frameshift_variant De novo NA Simplex 29346770 Takata A , et al. (2018)
c.228_232del p.Asp76GlufsTer20 frameshift_variant De novo NA - 28191889 Stessman HA , et al. (2017)
c.532_533del p.Gln178ThrfsTer5 frameshift_variant De novo NA - 28191889 Stessman HA , et al. (2017)
c.529del p.Thr177HisfsTer50 frameshift_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1697T>C p.Leu566Ser missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.532_533del p.Gln178ThrfsTer5 frameshift_variant De novo NA Multiplex 28263302 C Yuen RK , et al. (2017)
c.1009_1012delGAAA p.Glu337ArgfsTer5 frameshift_variant De novo NA Simplex 29656860 Cheng H , et al. (2018)
c.239_240del p.His80ArgfsTer17 frameshift_variant Familial Maternal Multiplex 29656860 Cheng H , et al. (2018)
CAAAGAAA>CAAA - frameshift_variant De novo NA Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.1988del p.Pro663ArgfsTer2 frameshift_variant Familial Maternal Multiplex 28191889 Stessman HA , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

A de novo loss-of-function (LoF) variant and a de novo missense variant that is predicted to be damaging were identified in the NAA15 gene in unrelated ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Furthermore, analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified NAA15 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene. Three novel de novo LoF variants in NAA15 were identified in probands reported to have a formal diagnosis of ASD in the Supplementary Material from Stessman et al., 2017 (PMID 28191889). An additional de novo LoF variant in NAA15 was identified in an ASD proband from a multiplex family by whole genome sequencing as part of the MSSNG initiative in Yuen et al., 2017 (PMID 28263302). Phenotypic characterization of 38 individuals from 33 unrelated families with de novo or inherited loss-of-function variants in NAA15, many of whom were previously unreported, identified recurrent phenotypes, including intellectual disability (23/23 cases, 100%), speech delay (32/33 cases, 97%), motor delay and related abnormalities (31/32 cases, 97%), ASD, ADHD, or behavioral issues (30/33 cases, 91%), and mild dysmorphic features (18/28 cases, 64%).

Score Delta: Score remained at 1S

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.

10/1/2019
1S
icon
1

Score remained at 1

New Scoring Scheme
Description

A de novo loss-of-function (LoF) variant and a de novo missense variant that is predicted to be damaging were identified in the NAA15 gene in unrelated ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Furthermore, analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified NAA15 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene. Three novel de novo LoF variants in NAA15 were identified in probands reported to have a formal diagnosis of ASD in the Supplementary Material from Stessman et al., 2017 (PMID 28191889). An additional de novo LoF variant in NAA15 was identified in an ASD proband from a multiplex family by whole genome sequencing as part of the MSSNG initiative in Yuen et al., 2017 (PMID 28263302). Phenotypic characterization of 38 individuals from 33 unrelated families with de novo or inherited loss-of-function variants in NAA15, many of whom were previously unreported, identified recurrent phenotypes, including intellectual disability (23/23 cases, 100%), speech delay (32/33 cases, 97%), motor delay and related abnormalities (31/32 cases, 97%), ASD, ADHD, or behavioral issues (30/33 cases, 91%), and mild dysmorphic features (18/28 cases, 64%).

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

Score remained at 1S

Description

A de novo loss-of-function (LoF) variant and a de novo missense variant that is predicted to be damaging were identified in the NAA15 gene in unrelated ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Furthermore, analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified NAA15 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene. Three novel de novo LoF variants in NAA15 were identified in probands reported to have a formal diagnosis of ASD in the Supplementary Material from Stessman et al., 2017 (PMID 28191889). An additional de novo LoF variant in NAA15 was identified in an ASD proband from a multiplex family by whole genome sequencing as part of the MSSNG initiative in Yuen et al., 2017 (PMID 28263302). Phenotypic characterization of 38 individuals from 33 unrelated families with de novo or inherited loss-of-function variants in NAA15, many of whom were previously unreported, identified recurrent phenotypes, including intellectual disability (23/23 cases, 100%), speech delay (32/33 cases, 97%), motor delay and related abnormalities (31/32 cases, 97%), ASD, ADHD, or behavioral issues (30/33 cases, 91%), and mild dysmorphic features (18/28 cases, 64%).

1/1/2019
1S
icon
1S

Score remained at 1S

Description

A de novo loss-of-function (LoF) variant and a de novo missense variant that is predicted to be damaging were identified in the NAA15 gene in unrelated ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Furthermore, analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified NAA15 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene. Three novel de novo LoF variants in NAA15 were identified in probands reported to have a formal diagnosis of ASD in the Supplementary Material from Stessman et al., 2017 (PMID 28191889). An additional de novo LoF variant in NAA15 was identified in an ASD proband from a multiplex family by whole genome sequencing as part of the MSSNG initiative in Yuen et al., 2017 (PMID 28263302). Phenotypic characterization of 38 individuals from 33 unrelated families with de novo or inherited loss-of-function variants in NAA15, many of whom were previously unreported, identified recurrent phenotypes, including intellectual disability (23/23 cases, 100%), speech delay (32/33 cases, 97%), motor delay and related abnormalities (31/32 cases, 97%), ASD, ADHD, or behavioral issues (30/33 cases, 91%), and mild dysmorphic features (18/28 cases, 64%).

10/1/2017
1
icon
1

Score remained at 1

Description

A de novo loss-of-function (LoF) variant and a de novo missense variant that is predicted to be damaging were identified in the NAA15 gene in unrelated ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Furthermore, analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified NAA15 as a gene meeting high statistical significance with a 0.05 < FDR ? 0.1, meaning that this gene had a ? 90% chance of being a true autism gene. Three novel de novo LoF variants in NAA15 were identified in probands reported to have a formal diagnosis of ASD in the Supplementary Material from Stessman et al., 2017 (PMID 28191889). An additional de novo LoF variant in NAA15 was identified in an ASD proband from a multiplex family by whole genome sequencing as part of the MSSNG initiative in Yuen et al., 2017 (PMID 28263302).

4/1/2017
1
icon
1

Score remained at 1

Description

A de novo LoF variant and a de novo missense variant that is predicted to be damaging were identified in the NAA15 gene in unrelated ASD probands from the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified NAA15 as a gene meeting high statistical significance with a 0.05< FDR ?0.1, meaning that this gene had a ?90% chance of being a true autism gene (PMID 25363760). Three novel de novo loss-of-function variants in NAA15 were identified in probands reported to have a formal diagnosis of ASD in the Supplementary Material from Stessman et al., 2017, bringing the total number of ASD-associated de novo LoF variants in NAA15 to four.

1/1/2017
3
icon
1

Decreased from 3 to 1

Description

A de novo LoF variant and a de novo missense variant that is predicted to be damaging were identified in the NAA15 gene in unrelated ASD probands from the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified NAA15 as a gene meeting high statistical significance with a 0.05 < FDR ?0.1, meaning that this gene had a ?90% chance of being a true autism gene (PMID 25363760). Three novel de novo loss-of-function variants in NAA15 were identified in probands reported to have a formal diagnosis of ASD in the Supplementary Material from Stessman et al., 2017, bringing the total number of ASD-associated de novo LoF variants in NAA15 to four.

1/1/2016
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant and a de novo missense variant that is predicted to be damaging were identified in the NAA15 gene in unrelated ASD probands from the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified NAA15 as a gene meeting high statistical significance with a 0.05

10/1/2014
icon
3

Increased from to 3

Description

A de novo LoF variant and a de novo missense variant that is predicted to be damaging were identified in the NAA15 gene in unrelated ASD probands from the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified NAA15 as a gene meeting high statistical significance with a 0.05

Krishnan Probability Score

Score 0.41096663316145

Ranking 22538/25841 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 0.99857683950162

Ranking 1159/18225 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 0.85

Ranking 192/239 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 0.080859743759523

Ranking 58/18665 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 11.5

Ranking 168/461 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 0.30241539369242

Ranking 2706/20870 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.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
C15ORF63 Huntingtin-interacting protein K Human Protein Binding 25764 Q9NX55
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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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