Human Gene Module / Chromosome 20 / RALGAPB

RALGAPBRal GTPase activating protein non-catalytic beta subunit

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
5 / 6
Rare Variants / Common Variants
16 / 0
Aliases
RALGAPB, KIAA1219,  RalGAPbeta
Associated Syndromes
-
Chromosome Band
20q11.23
Associated Disorders
-
Relevance to Autism

Two de novo frameshift variants and one de novo missense variant in the RALGAPB gene were identified in ASD probands in De Rubeis et al., 2014 and Guo et al., 2018. A de novo nonsense variant in this gene had previously been identified in a patient with epileptic encephalopathy (Epi4K Consortium 2013). An additional de novo likely gene-disruptive variant in the RALGAPB gene was identified in an ASD proband from the SPARK cohort in Feliciano et al., 2019. Three additional de novo loss-of-function variants in the RALGAPB 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 RALGAPB as a gene reaching study-wide significance based on 5,754 constraint genes (P < 8.69E-06).

Molecular Function

Non-catalytic subunit of the heterodimeric RalGAP1 and RalGAP2 complexes which act as GTPase activators for the Ras-like small GTPases RALA and RALB.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to RALGAPB (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support De novo mutations in epileptic encephalopathies Epi4K Consortium , et al. (2013) No -
2 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
3 Recent Recommendation Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
4 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
5 Support Excess of RALGAPB de novo variants in neurodevelopmental disorders Shah AA et al. (2020) Yes -
6 Support - Zhou X et al. (2022) Yes -
Rare Variants   (16)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.3818-1G>A - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.2413C>T p.Arg805Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.3984G>C p.Leu1328= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.974A>G p.Tyr325Cys missense_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.1791A>T p.Glu597Asp missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.3423G>A p.Thr1141= synonymous_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.1928dup p.Asn643LysfsTer3 frameshift_variant De novo - - 30564305 Guo H , et al. (2018)
c.1238C>T p.Thr413Met missense_variant De novo - Simplex 32853829 Shah AA et al. (2020)
c.1573dup p.Cys525LeufsTer2 frameshift_variant De novo - - 31452935 Feliciano P et al. (2019)
c.3259_3263del p.Arg1087PhefsTer3 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.3860C>G p.Ser1287Ter stop_gained De novo - Simplex 23934111 Epi4K Consortium , et al. (2013)
c.523G>A p.Asp175Asn missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.1010G>A p.Arg337His missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.2731G>A p.Gly911Ser missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.865_866del p.Met289ValfsTer3 frameshift_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.4376G>A p.Arg1459Gln missense_variant Unknown Not paternal Simplex 30564305 Guo H , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

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.

7/1/2020
1
icon
1

Score remained at 1

Description

Two de novo frameshift variants and one de novo missense variant in the RALGAPB gene were identified in ASD probands in De Rubeis et al., 2014 and Guo et al., 2018. A de novo nonsense variant in this gene had previously been identified in a patient with epileptic encephalopathy (Epi4K Consortium 2013). An additional de novo likely gene-disruptive variant in the RALGAPB gene was identified in an ASD proband from the SPARK cohort in Feliciano et al., 2019.

Reports Added
[Excess of RALGAPB de novo variants in neurodevelopmental disorders2020]
10/1/2019
3
icon
1

Decreased from 3 to 1

New Scoring Scheme
Description

Two de novo frameshift variants and one de novo missense variant in the RALGAPB gene were identified in ASD probands in De Rubeis et al., 2014 and Guo et al., 2018. A de novo nonsense variant in this gene had previously been identified in a patient with epileptic encephalopathy (Epi4K Consortium 2013). An additional de novo likely gene-disruptive variant in the RALGAPB gene was identified in an ASD proband from the SPARK cohort in Feliciano et al., 2019.

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
1/1/2019
icon
3

Increased from to 3

Description

Two de novo frameshift variants and one de novo missense variant in the RALGAPB gene were identified in ASD probands in De Rubeis et al., 2014 and Guo et al., 2018. A de novo nonsense variant in this gene had previously been identified in a patient with epileptic encephalopathy (Epi4K Consortium 2013).

Krishnan Probability Score

Score 0.33679581133934

Ranking 24333/25841 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 0.99999995563256

Ranking 168/18225 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 0.56017799159087

Ranking 591/18665 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 0.37467875662867

Ranking 1733/20870 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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