Human Gene Module / Chromosome 4 / LRBA

LRBALPS-responsive vesicle trafficking, beach and anchor containing

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
9 / 10
Rare Variants / Common Variants
21 / 0
Aliases
LRBA, BGL,  CDC4L,  CVID8,  LAB300,  LBA
Associated Syndromes
-
Chromosome Band
4q31.3
Associated Disorders
-
Relevance to Autism

This gene was identified as a novel ASD candidate gene in Gonzalez-Mantilla et al., 2016 based on the presence of two potentially pathogenic loss-of-function variants in ASD cases (single gene deletions of unknown origin in probands from AGRE and the Simons Simplex Collection in Gai et al., 2012 and Girirajan et al., 2013, respectively).

Molecular Function

May be involved in coupling signal transduction and vesicle trafficking to enable polarized secretion and/or membrane deposition of immune effector molecules.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to LRBA (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Rare structural variation of synapse and neurotransmission genes in autism Gai X , et al. (2011) Yes -
2 Support Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder Girirajan S , et al. (2013) Yes -
3 Recent Recommendation A Cross-Disorder Method to Identify Novel Candidate Genes for Developmental Brain Disorders Gonzalez-Mantilla AJ , et al. (2016) No -
4 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
5 Support Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder Krupp DR , et al. (2017) Yes -
6 Support Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort Wu H , et al. (2019) Yes Macrocephaly
7 Support - Woodbury-Smith M et al. (2022) Yes -
8 Support - Zhou X et al. (2022) Yes -
9 Support - Cirnigliaro M et al. (2023) Yes -
10 Support - Soo-Whee Kim et al. (2024) Yes -
Rare Variants   (21)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Unknown - - 21358714 Gai X , et al. (2011)
- - copy_number_loss Unknown - Simplex 23375656 Girirajan S , et al. (2013)
c.7042C>G p.Arg2348Gly missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.8083G>A p.Gly2695Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4920G>A p.Val1640%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.8550C>T p.Asn2850%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.412C>T p.Leu138Phe missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.4688G>A p.Cys1563Tyr missense_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.5492G>A p.Gly1831Glu missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.5809C>T p.His1937Tyr missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.6363A>C p.Lys2121Asn missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.6659C>T p.Thr2220Met missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.7196C>T p.Thr2399Ile missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.7286C>T p.Ala2429Val missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.7888G>A p.Val2630Ile missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.8084C>T p.Ala2695Val missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.4788C>A p.Ser1596Arg missense_variant De novo - Simplex 28867142 Krupp DR , et al. (2017)
c.8458T>C p.Cys2820Arg missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.2020G>T p.Glu674Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.2591_2592del p.Ser864CysfsTer13 frameshift_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.4427del p.His1476LeufsTer6 frameshift_variant Familial Maternal Simplex 31674007 Wu H , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

This gene was identified as a novel ASD candidate gene in Gonzalez-Mantilla et al., 2016 based on the presence of two potentially pathogenic loss-of-function variants in ASD cases (single gene deletions of unknown origin in probands from AGRE and the Simons Simplex Collection in Gai et al., 2012 and Girirajan et al., 2013, respectively).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

This gene was identified as a novel ASD candidate gene in Gonzalez-Mantilla et al., 2016 based on the presence of two potentially pathogenic loss-of-function variants in ASD cases (single gene deletions of unknown origin in probands from AGRE and the Simons Simplex Collection in Gai et al., 2012 and Girirajan et al., 2013, respectively).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

This gene was identified as a novel ASD candidate gene in Gonzalez-Mantilla et al., 2016 based on the presence of two potentially pathogenic loss-of-function variants in ASD cases (single gene deletions of unknown origin in probands from AGRE and the Simons Simplex Collection in Gai et al., 2012 and Girirajan et al., 2013, respectively).

Reports Added
[Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort.2019] [New Scoring Scheme]
10/1/2017
4
icon
4

Decreased from 4 to 4

Description

This gene was identified as a novel ASD candidate gene in Gonzalez-Mantilla et al., 2016 based on the presence of two potentially pathogenic loss-of-function variants in ASD cases (single gene deletions of unknown origin in probands from AGRE and the Simons Simplex Collection in Gai et al., 2012 and Girirajan et al., 2013, respectively).

Reports Added
[Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.2017] [Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder.2017]
1/1/2016
icon
4

Increased from to 4

Description

This gene was identified as a novel ASD candidate gene in Gonzalez-Mantilla et al., 2016 based on the presence of two potentially pathogenic loss-of-function variants in ASD cases (single gene deletions of unknown origin in probands from AGRE and the Simons Simplex Collection in Gai et al., 2012 and Girirajan et al., 2013, respectively).

Krishnan Probability Score

Score 0.48594611212205

Ranking 7269/25841 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 0.044229436613441

Ranking 8682/18225 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
Sanders TADA Score

Score 0.94670999708192

Ranking 16980/18665 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 0.41722378534602

Ranking 1264/20870 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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