Human Gene Module / Chromosome 13 / NBEA

NBEAneurobeachin

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
7 / 18
Rare Variants / Common Variants
26 / 0
Aliases
NBEA, BCL8B,  LYST2
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Chromosome Band
13q13.3
Associated Disorders
EPS, ASD
Relevance to Autism

Rare mutation in the NBEA gene has been identified with idiopathic autism (Castermans et al., 2003).

Molecular Function

The encoded protein has protein kinase A binding activity.

Reports related to NBEA (18 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Neurobeachin: A protein kinase A-anchoring, beige/Chediak-higashi protein homolog implicated in neuronal membrane traffic. Wang X , et al. (2000) No -
2 Primary The neurobeachin gene is disrupted by a translocation in a patient with idiopathic autism. Castermans D , et al. (2003) Yes -
3 Support Molecular genetic delineation of a deletion of chromosome 13q12-->q13 in a patient with autism and auditory processing deficits. Smith M , et al. (2003) Yes -
4 Recent Recommendation The neurobeachin gene spans the common fragile site FRA13A. Savelyeva L , et al. (2005) No -
5 Recent Recommendation SEL-2, the C. elegans neurobeachin/LRBA homolog, is a negative regulator of lin-12/Notch activity and affects endosomal traffic in polarized epithe... de Souza N , et al. (2007) No -
6 Support Neurobeachin, a protein implicated in membrane protein traffic and autism, is required for the formation and functioning of central synapses. Medrihan L , et al. (2009) No -
7 Support The autism candidate gene Neurobeachin encodes a scaffolding protein implicated in membrane trafficking and signaling. Volders K , et al. (2011) No -
8 Support Dendritic spine formation and synaptic function require neurobeachin. Niesmann K , et al. (2011) No -
9 Support Haploinsufficiency of the autism candidate gene Neurobeachin induces autism-like behaviors and affects cellular and molecular processes of synaptic... Nuytens K , et al. (2012) No -
10 Support Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
11 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
12 Support Drosophila mutants of the autism candidate gene neurobeachin (rugose) exhibit neuro-developmental disorders, aberrant synaptic properties, altered ... Wise A , et al. (2015) No -
13 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
14 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) No -
15 Recent Recommendation NBEA: Developmental disease gene with early generalized epilepsy phenotypes. Mulhern MS , et al. (2018) No ASD or autistic features, epilepsy/seizures
16 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model. Guo H , et al. (2018) Yes -
17 Support Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort. Callaghan DB , et al. (2019) Yes -
18 Support Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing. Bruel AL , et al. (2019) No -
Rare Variants   (26)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 30269351 Mulhern MS , et al. (2018)
- - translocation De novo - Simplex 12746398 Castermans D , et al. (2003)
c.7707+2T>C p.? splice_site_variant De novo - - 31231135 Bruel AL , et al. (2019)
c.1006C>T p.Arg336Ter stop_gained De novo - - 30269351 Mulhern MS , et al. (2018)
c.6637C>T p.Arg2213Ter stop_gained Unknown - - 28554332 Bowling KM , et al. (2017)
c.3832C>T p.Arg1278Ter stop_gained De novo - - 30269351 Mulhern MS , et al. (2018)
c.4715C>A p.Ser1572Ter stop_gained De novo - - 30269351 Mulhern MS , et al. (2018)
c.6313G>T p.Glu2105Ter stop_gained De novo - - 30269351 Mulhern MS , et al. (2018)
c.6829C>T p.Arg2277Ter stop_gained De novo - - 30269351 Mulhern MS , et al. (2018)
c.6868C>T p.Gln2290Ter stop_gained De novo - - 30269351 Mulhern MS , et al. (2018)
c.7462G>T p.Glu2488Ter stop_gained De novo - - 30269351 Mulhern MS , et al. (2018)
c.7707+2T>C p.? splice_site_variant De novo - - 30269351 Mulhern MS , et al. (2018)
c.2836C>T p.His946Tyr missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.1448C>T p.Ala483Val missense_variant De novo - - 30269351 Mulhern MS , et al. (2018)
c.3994C>T p.Pro1332Ser missense_variant De novo - - 30269351 Mulhern MS , et al. (2018)
c.8401G>A p.Glu2801Lys missense_variant De novo - - 30269351 Mulhern MS , et al. (2018)
c.7381G>A p.Val2461Met missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.6829C>T p.Arg2277Ter stop_gained De novo - Simplex 25363768 Iossifov I , et al. (2014)
T>G p.Asp378Glu missense_variant Unknown - Simplex 31038196 Callaghan DB , et al. (2019)
c.3362del p.Asn1121MetfsTer9 frameshift_variant De novo - - 30269351 Mulhern MS , et al. (2018)
c.782C>T p.Thr261Ile missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.4484del p.Asn1495IlefsTer17 frameshift_variant De novo - - 30269351 Mulhern MS , et al. (2018)
c.7230del p.Asp2411IlefsTer21 frameshift_variant De novo - - 30269351 Mulhern MS , et al. (2018)
c.3183delA p.Glu1062ArgfsTer8 frameshift_variant De novo - - 30269351 Mulhern MS , et al. (2018)
c.7294_7295dup p.Glu2433ArgfsTer3 frameshift_variant De novo - - 30269351 Mulhern MS , et al. (2018)
c.[851G>A];[851G>A] p.[Arg284His];[Arg284His] missense_variant;missense_variant Familial Both parents Simplex 30564305 Guo H , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Smith et al., 2002 identified a large de novo 13q12-q13 deletion that included the NBEA gene in a sporadic case of autism and language deficit due to auditory processing defects. Castermans et al., 2003 reported that the NBEA gene was disrupted by a de novo balanced translocation in a patient with idiopathic autism. Subsequent studies demonstrated that neurobeachin, the protein encoded by the NBEA gene, was required for synapse formation and function (Medrihan et al., 2009; Volders et al., 2011; Niesmann et al., 2011). Two de novo variants in the NBEA gene (one loss-of-function, one missense variant predicted to be benign) were identified in ASD probands from the Simons Simplex Collection and Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014). Phenotypic characterization of 24 individuals with NBEA variants in Mulhern et al., 2018 (22 previously unreported cases and two cases previously reported in Bowling et al., 2017) determined that 12 out of 24 patients had a diagnosis of ASD or prominent autistic features. The potential role of NEBA in autism and other neurodevelopmental disorders has been further supported by functional studies in mice and Drosophila (Nuytens et al., 2013; Wise et al., 2015).

Score Delta: Score remained at 4S

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.

7/1/2019
4S
icon
4S

Score remained at 4S

Description

Smith et al., 2002 identified a large de novo 13q12-q13 deletion that included the NBEA gene in a sporadic case of autism and language deficit due to auditory processing defects. Castermans et al., 2003 reported that the NBEA gene was disrupted by a de novo balanced translocation in a patient with idiopathic autism. Subsequent studies demonstrated that neurobeachin, the protein encoded by the NBEA gene, was required for synapse formation and function (Medrihan et al., 2009; Volders et al., 2011; Niesmann et al., 2011). Two de novo variants in the NBEA gene (one loss-of-function, one missense variant predicted to be benign) were identified in ASD probands from the Simons Simplex Collection and Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014). Phenotypic characterization of 24 individuals with NBEA variants in Mulhern et al., 2018 (22 previously unreported cases and two cases previously reported in Bowling et al., 2017) determined that 12 out of 24 patients had a diagnosis of ASD or prominent autistic features. The potential role of NEBA in autism and other neurodevelopmental disorders has been further supported by functional studies in mice and Drosophila (Nuytens et al., 2013; Wise et al., 2015).

4/1/2019
4S
icon
4S

Score remained at 4S

Description

2019 Q3 Rescoring regime

1/1/2019
4S
icon
4S

Score remained at 4S

Description

Smith et al., 2002 identified a large de novo 13q12-q13 deletion that included the NBEA gene in a sporadic case of autism and language deficit due to auditory processing defects. Castermans et al., 2003 reported that the NBEA gene was disrupted by a de novo balanced translocation in a patient with idiopathic autism. Subsequent studies demonstrated that neurobeachin, the protein encoded by the NBEA gene, was required for synapse formation and function (Medrihan et al., 2009; Volders et al., 2011; Niesmann et al., 2011). Two de novo variants in the NBEA gene (one loss-of-function, one missense variant predicted to be benign) were identified in ASD probands from the Simons Simplex Collection and Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014). Phenotypic characterization of 24 individuals with NBEA variants in Mulhern et al., 2018 (22 previously unreported cases and two cases previously reported in Bowling et al., 2017) determined that 12 out of 24 patients had a diagnosis of ASD or prominent autistic features. The potential role of NEBA in autism and other neurodevelopmental disorders has been further supported by functional studies in mice and Drosophila (Nuytens et al., 2013; Wise et al., 2015).

10/1/2018
4
icon
4S

Score remained at 4S

Description

Smith et al., 2002 identified a large de novo 13q12-q13 deletion that included the NBEA gene in a sporadic case of autism and language deficit due to auditory processing defects. Castermans et al., 2003 reported that the NBEA gene was disrupted by a de novo balanced translocation in a patient with idiopathic autism. Subsequent studies demonstrated that neurobeachin, the protein encoded by the NBEA gene, was required for synapse formation and function (Medrihan et al., 2009; Volders et al., 2011; Niesmann et al., 2011). Two de novo variants in the NBEA gene (one loss-of-function, one missense variant predicted to be benign) were identified in ASD probands from the Simons Simplex Collection and Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014). Phenotypic characterization of 24 individuals with NBEA variants in Mulhern et al., 2018 (22 previously unreported cases and two cases previously reported in Bowling et al., 2017) determined that 12 out of 24 patients had a diagnosis of ASD or prominent autistic features. The potential role of NEBA in autism and other neurodevelopmental disorders has been further supported by functional studies in mice and Drosophila (Nuytens et al., 2013; Wise et al., 2015).

7/1/2014
No data
icon
4

Increased from No data to 4

Description

There is minimal evidence for NBEA. The gene is within a large de novo deletion seen in a patient with autism. A second report found that the NBEA gene was disrupted by a balanced translocation in a patient with autism.

4/1/2014
No data
icon
4

Increased from No data to 4

Description

There is minimal evidence for NBEA. The gene is within a large de novo deletion seen in a patient with autism. A second report found that the NBEA gene was disrupted by a balanced translocation in a patient with autism.

Krishnan Probability Score

Score 0.73782230680382

Ranking 37/25841 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 0.99999999999998

Ranking 21/18225 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 0.984

Ranking 38/239 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 0.62621507841437

Ranking 801/18665 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).
Zhang D Score

Score 0.61911298093436

Ranking 51/20870 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
Ascl1 achaete-scute family bHLH transcription factor 1 Mouse Protein Binding 17172 Q02067
Atpif1 ATPase inhibitory factor 1 Mouse Protein Binding 11983 O35143
Fam58b family with sequence similarity 58, member B Mouse Protein Binding 69109 Q8QZR8
Fam96b family with sequence similarity 96, member B Mouse Protein Binding 68523 Q9D187
Igfbp5 insulin-like growth factor binding protein 5 Mouse Protein Binding 16011 Q07079
Kansl1l KAT8 regulatory NSL complex subunit 1-like Mouse Protein Binding 68691 Q5DTI6
Kif4 kinesin family member 4 Mouse Protein Binding 16571 P33174
Ppp2r3c protein phosphatase 2, regulatory subunit B'', gamma Mouse Protein Binding 59032 Q9JK24
RD3 Protein RD3 Human Protein Binding 343035 Q7Z3Z2
Sox7 SRY (sex determining region Y)-box 7 Mouse Protein Binding 20680 P40646
Tmem181a transmembrane protein 181A Mouse Protein Binding 77106 Q3U3W2
Upk1a uroplakin 1A Mouse Protein Binding 109637 Q9D132
Wdr31 WD repeat domain 31 Mouse Protein Binding 71354 Q9JHB4
Zfp287 zinc finger protein 287 Mouse Protein Binding 170740 Q9EQB9
Zfp748 zinc finger protein 748 Mouse Protein Binding 212276 Q3V1X2
Zfp827 zinc finger protein 827 Mouse Protein Binding 622675 Q505G8
Zfp865 zinc finger protein 865 Mouse Protein Binding 319748 Q3U3I9
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