Human Gene Module / Chromosome 11 / APBB1

APBB1amyloid beta precursor protein binding family B member 1

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
3 / 3
Rare Variants / Common Variants
3 / 0
Aliases
APBB1, FE65,  MGC:9072,  RIR
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Functional
Chromosome Band
11p15.4
Associated Disorders
-
Relevance to Autism

A de novo loss-of-function variant in the APBB1 gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. TADA-Annotations (TADA-A) analysis of whole-genome sequencing data from five studies with a total of 314 ASD-affected subjects in Liu et al., 2018 identified APBB1 as an ASD risk gene with a false discovery rate (FDR) < 0.1; among the de novo variants associated with this gene in ASD subjects was a loss-of-function variant, a regulatory SNV, and two conserved regulatory SNVs. APBB1 expression had previously been shown to be significantly down-regulated in the cerebellum of autistic patients (Zeidn-Chuli et al., 2014).

Molecular Function

Transcription coregulator that can have both coactivator and corepressor functions. Adapter protein that forms a transcriptionally active complex with the gamma-secretase-derived amyloid precursor protein (APP) intracellular domain.

Reports related to APBB1 (3 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Altered expression of Alzheimer's disease-related genes in the cerebellum of autistic patients: a model for disrupted brain connectome and therapy. Zeidn-Chuli F , et al. (2014) Yes -
2 Primary The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
3 Recent Recommendation A Statistical Framework for Mapping Risk Genes from De Novo Mutations in Whole-Genome-Sequencing Studies. Liu Y , et al. (2018) Yes -
Rare Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - loss_of_function_variant De novo NA - 29754769 Liu Y , et al. (2018)
- - regulatory_region_variant De novo NA - 29754769 Liu Y , et al. (2018)
c.1693dup p.Ala565GlyfsTer12 frameshift_variant De novo NA Simplex 25363768 Iossifov I , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo loss-of-function variant in the APBB1 gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. TADA-Annotations (TADA-A) analysis of whole-genome sequencing data from five studies with a total of 314 ASD-affected subjects in Liu et al., 2018 identified APBB1 as an ASD risk gene with a false discovery rate (FDR) < 0.1; among the de novo variants associated with this gene in ASD subjects was a loss-of-function variant, a regulatory SNV, and two conserved regulatory SNVs. APBB1 expression had previously been shown to be significantly down-regulated in the cerebellum of autistic patients (Zeidn-Chuli et al., 2014).

Score Delta: Decreased from 3 to 2

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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

A de novo loss-of-function variant in the APBB1 gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. TADA-Annotations (TADA-A) analysis of whole-genome sequencing data from five studies with a total of 314 ASD-affected subjects in Liu et al., 2018 identified APBB1 as an ASD risk gene with a false discovery rate (FDR) < 0.1; among the de novo variants associated with this gene in ASD subjects was a loss-of-function variant, a regulatory SNV, and two conserved regulatory SNVs. APBB1 expression had previously been shown to be significantly down-regulated in the cerebellum of autistic patients (Zeidn-Chuli et al., 2014).

Reports Added
[New Scoring Scheme]
4/1/2018
icon
3.3

Increased from to 3.3

Description

3

Krishnan Probability Score

Score 0.49710990505783

Ranking 2444/25841 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 0.98699365222094

Ranking 1929/18225 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
Sanders TADA Score

Score 0.48742716493548

Ranking 422/18665 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 0.36195872581836

Ranking 1878/20870 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.
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