Human Gene Module / Chromosome 4 / NAA15

NAA15N(alpha)-acetyltransferase 15, NatA auxiliary subunit

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
13 / 26
Rare Variants / Common Variants
99 / 0
EAGLE Score
31.7
Strong Learn More
Aliases
NAA15, Ga19,  NARG1,  NAT1P,  NATH,  TBDN,  TBDN100
Associated Syndromes
-
Chromosome Band
4q31.1
Associated Disorders
ADHD, ID, ASD, EPS
Genetic Category
Rare Single Gene Mutation, Syndromic
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). 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%). Two additional de novo loss-of-function variants in the NAA15 gene were reported in ASD probands from the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified NAA15 as a gene reaching exome-wide significance (P < 2.5E-06).

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.

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 NAA15 (26 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 -
14 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
15 Support - Tian Y et al. (2022) No ADHD
16 Support - Chuan Z et al. (2022) No ID
17 Support - Zhou X et al. (2022) Yes -
18 Support - Spataro N et al. (2023) No -
19 Support - Lyon GJ et al. (2023) No ASD or autistic behavior, ADHD, epilepsy/seizures,
20 Support - Cirnigliaro M et al. (2023) Yes -
21 Support - Amerh S Alqahtani et al. (2023) No -
22 Support - Karthika Ajit Valaparambil et al. () Yes -
23 Recent Recommendation - Kuokuo Li et al. (2024) Yes -
24 Support - Tamam Khalaf et al. (2024) No -
25 Support - Axel Schmidt et al. (2024) No Cognitive impairment
26 Support - Karen Lob et al. () Yes DD
Rare Variants   (99)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - - 29621621 Pesz K , et al. (2018)
c.232A>T p.Lys78Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.908-2A>G - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.1014+1G>C - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.517G>T p.Glu173Ter stop_gained De novo - - 37130971 Lyon GJ et al. (2023)
c.852G>A p.Trp284Ter stop_gained Unknown - - 37130971 Lyon GJ et al. (2023)
c.1753+1G>A - splice_site_variant Unknown - - 37130971 Lyon GJ et al. (2023)
c.908-2A>G - splice_site_variant De novo - - 29656860 Cheng H , et al. (2018)
c.1861C>T p.Gln621Ter stop_gained De novo - - 37130971 Lyon GJ et al. (2023)
c.2344C>T p.Arg782Ter stop_gained De novo - - 37130971 Lyon GJ et al. (2023)
c.913A>T p.Lys305Ter stop_gained De novo - - 29656860 Cheng H , et al. (2018)
c.1087+2T>C - splice_site_variant De novo - - 29656860 Cheng H , et al. (2018)
c.1906G>T p.Gly636Ter stop_gained De novo - - 29656860 Cheng H , et al. (2018)
c.305G>A p.Cys102Tyr missense_variant De novo - - 39136901 Karen Lob et al. ()
c.79A>G p.Arg27Gly missense_variant De novo - - 37130971 Lyon GJ et al. (2023)
c.1031A>T p.Glu344Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1513C>T p.Leu505Phe missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1643T>G p.Leu548Arg missense_variant De novo - - 33004838 Wang T et al. (2020)
c.2326G>T p.Asp776Tyr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.868G>T p.Gly290Ter stop_gained Unknown - - 28191889 Stessman HA , et al. (2017)
c.382C>T p.Arg128Ter stop_gained De novo - - 39039281 Axel Schmidt et al. (2024)
c.430C>T p.Arg144Ter stop_gained De novo - - 39039281 Axel Schmidt et al. (2024)
c.1540-1G>A - splice_site_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.1410+5G>C - splice_site_variant De novo - Simplex 35328089 Tian Y et al. (2022)
c.1753G>A p.Ala585Thr missense_variant De novo - - 37130971 Lyon GJ et al. (2023)
c.2155G>A p.Ala719Thr missense_variant De novo - - 37130971 Lyon GJ et al. (2023)
c.2591A>G p.Asn864Ser missense_variant De novo - - 37130971 Lyon GJ et al. (2023)
c.2086A>T p.Lys696Ter stop_gained De novo - - 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.1819C>T p.Gln607Ter stop_gained De novo - Simplex 35328089 Tian Y et al. (2022)
c.1413A>C p.Glu471Asp missense_variant De novo - - 31127942 Cheng H , et al. (2019)
c.1450T>C p.Cys484Arg missense_variant De novo - - 31127942 Cheng H , et al. (2019)
c.232A>T p.Lys78Ter stop_gained Unknown - Simplex 29656860 Cheng H , et al. (2018)
c.248G>A p.Trp83Ter stop_gained De novo - Simplex 29656860 Cheng H , et al. (2018)
c.2057-1G>C - splice_site_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.74A>C p.Gln25Pro missense_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.2300C>A p.Ser767Ter stop_gained De novo - Simplex 29656860 Cheng H , et al. (2018)
c.2322C>G p.Tyr774Ter stop_gained De novo - 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.1424C>T p.Ala475Val missense_variant Unknown - - 28191889 Stessman HA , et al. (2017)
c.154A>T p.Lys52Ter stop_gained Unknown - Simplex 28191889 Stessman HA , et al. (2017)
c.818del p.Met273SerfsTer2 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.1321G>A p.Asp441Asn missense_variant De novo - Simplex 35328089 Tian Y et al. (2022)
c.309C>G p.Tyr103Ter stop_gained De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.2061del p.Lys687AsnfsTer4 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.1786C>T p.Arg596Cys missense_variant De novo - Simplex 35571021 Chuan Z et al. (2022)
c.841G>C p.Glu281Gln missense_variant De novo - Simplex 28990276 Zhao JJ , et al. (2017)
c.1741G>A p.Glu581Lys missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.517del p.Glu173AsnfsTer54 frameshift_variant De novo - - 37130971 Lyon GJ et al. (2023)
c.986dup p.Leu329PhefsTer22 frameshift_variant De novo - - 37130971 Lyon GJ et al. (2023)
c.1051del p.Thr351ProfsTer3 frameshift_variant De novo - - 37130971 Lyon GJ et al. (2023)
c.2031dup p.Ala678CysfsTer3 frameshift_variant De novo - - 37130971 Lyon GJ et al. (2023)
c.2441T>C p.Leu814Pro missense_variant De novo - Simplex 31127942 Cheng H , et al. (2019)
c.287dup p.Tyr96Ter frameshift_variant De novo - Simplex 29656860 Cheng H , et al. (2018)
c.1540-1G>T - splice_site_variant Familial Maternal Simplex 35328089 Tian Y et al. (2022)
c.1083del p.Asn362MetfsTer36 frameshift_variant De novo - - 37130971 Lyon GJ et al. (2023)
c.1868del p.Asn623IlefsTer13 frameshift_variant De novo - - 37130971 Lyon GJ et al. (2023)
c.420dup p.Leu141ThrfsTer25 frameshift_variant De novo - - 29656860 Cheng H , et al. (2018)
c.1413A>C p.Glu471Asp missense_variant De novo - Simplex 31130284 Monies D , et al. (2019)
c.1695T>A p.Tyr565Ter stop_gained De novo - Multiplex 28191889 Stessman HA , et al. (2017)
c.228_232del p.Asp76GlufsTer20 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.532_533del p.Gln178ThrfsTer5 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.1841del p.Asn614MetfsTer22 frameshift_variant De novo - - 29656860 Cheng H , et al. (2018)
c.239_240del p.His80ArgfsTer17 frameshift_variant De novo - - 37130971 Lyon GJ et al. (2023)
c.228_232del p.Asp76GlufsTer20 frameshift_variant De novo - - 29656860 Cheng H , et al. (2018)
c.239_240del p.His80ArgfsTer17 frameshift_variant De novo - - 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.1014G>T p.Lys338Asn missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
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.1009_1012del p.Glu337ArgfsTer5 frameshift_variant De novo - - 29656860 Cheng H , et al. (2018)
c.1795_1798del p.Gln599GlufsTer9 frameshift_variant Unknown - - 29656860 Cheng H , et al. (2018)
c.1798_1801del p.Arg600GlufsTer8 frameshift_variant De novo - - 29656860 Cheng H , et al. (2018)
c.163del p.Thr55HisfsTer2 frameshift_variant De novo - Simplex 29656860 Cheng H , et al. (2018)
c.1348A>G p.Lys450Glu missense_variant Familial Paternal - 28191889 Stessman HA , et al. (2017)
c.1446dup p.Gln483AlafsTer14 frameshift_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.1144C>A p.Gln382Lys missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.1798_1801del p.Arg600GlufsTer8 frameshift_variant Unknown - - 36980980 Spataro N et al. (2023)
c.2108C>G p.Ser703Cys missense_variant Unknown - - 37943464 Karthika Ajit Valaparambil et al. ()
c.228_232del p.Asp76GlufsTer20 frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.239_240del p.His80ArgfsTer17 frameshift_variant Unknown - - 28191889 Stessman HA , et al. (2017)
c.532_533del p.Gln178ThrfsTer5 frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.264del p.Leu89PhefsTer19 frameshift_variant De novo - Multiplex 29346770 Takata A , et al. (2018)
c.1798_1801del p.Arg600GlufsTer8 frameshift_variant Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.239_240del p.His80ArgfsTer17 frameshift_variant De novo - Simplex 29656860 Cheng H , et al. (2018)
c.239_240del p.His80ArgfsTer17 frameshift_variant Unknown - Unknown 29656860 Cheng H , et al. (2018)
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 - Multiplex 28263302 C Yuen RK et al. (2017)
c.2344C>T p.Arg782Ter stop_gained Familial Paternal Multiplex 37799141 Amerh S Alqahtani et al. (2023)
c.1624_1627delinsAT p.Leu542IlefsTer28 frameshift_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.1009_1012delGAAA p.Glu337ArgfsTer5 frameshift_variant De novo - Simplex 29656860 Cheng H , et al. (2018)
c.228_232del p.Asp76GlufsTer20 frameshift_variant De novo - Multiplex 37506195 Cirnigliaro M et al. (2023)
CAAAGAAA>CAAA - frameshift_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.239_240del p.His80ArgfsTer17 frameshift_variant Familial Maternal Multiplex 29656860 Cheng H , et al. (2018)
c.1988del p.Pro663ArgfsTer2 frameshift_variant Familial Maternal Multiplex 28191889 Stessman HA , et al. (2017)
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."

10/1/2020
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). 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
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
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%).

Reports Added
[Phenotypic and biochemical analysis of an international cohort of individuals with variants in NAA10 and NAA15.2019] [Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.2019] [Autism-associated missense genetic variants impact locomotion and neurodevelopment in Caenorhabditis elegans.2019]
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%).

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

Reports Added
[Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability.2017]
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.

Reports Added
[Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017]
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.

Reports Added
[Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017]
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

Reports Added
[Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
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.
Original Source
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
Original Source
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
Original Source
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).
Original Source
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.
Original Source
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.
Original Source
Interactome
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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