Human Gene Module / Chromosome 7 / RALA

RALARAS like proto-oncogene A

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
5 / 6
Rare Variants / Common Variants
14 / 0
Aliases
RALA, RAL
Associated Syndromes
-
Chromosome Band
7p14.1
Associated Disorders
ASD, EPS
Relevance to Autism

Hiatt et al., 2018 described a cohort of ten cases with de novo protein-altering variants in the RALA gene presenting with a neurodevelopmental disorder characterized by developmental delay/intellectual disability, delayed or absent speech, hypotonia, inability to walk, facial dysmorphism, short stature, decreased body weight, and abnormal brain MRI; 3/3 individuals in this cohort for whom information was available also presented with ASD. The same de novo missense variant that was observed in all three ASD cases in Hiatt et al., 2018 (c.73G>A;p.Val25Met) was also observed in a Japanese patient diagnosed with autism spectrum disorder and presenting with a Noonan syndrome-like phenotype in Okamoto et al., 2019.

Molecular Function

Multifunctional GTPase involved in a variety of cellular processes including gene expression, cell migration, cell proliferation, oncogenic transformation and membrane trafficking.

External Links
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Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to RALA (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
2 Primary De novo mutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay Hiatt SM , et al. (2018) No ASD, epilepsy/seizures
3 Support RALA mutation in a patient with autism spectrum disorder and Noonan syndrome-like phenotype Okamoto N , et al. (2019) Yes Noonan-like syndrome
4 Support - Bertoli-Avella AM et al. (2021) Yes -
5 Support - Mahjani B et al. (2021) Yes -
6 Support - Zhou X et al. (2022) Yes -
Rare Variants   (14)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - missense_variant De novo - - 30500825 Hiatt SM , et al. (2018)
- - missense_variant De novo - - 30761613 Okamoto N , et al. (2019)
- - missense_variant De novo - Simplex 30500825 Hiatt SM , et al. (2018)
c.526C>T p.Arg176Ter stop_gained Unknown - - 30500825 Hiatt SM , et al. (2018)
c.469T>A p.Ser157Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.73G>A p.Val25Met missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
- - missense_variant De novo - Multi-generational 30500825 Hiatt SM , et al. (2018)
c.383A>G p.Lys128Arg missense_variant De novo - - 30500825 Hiatt SM , et al. (2018)
c.389A>G p.Asp130Gly missense_variant De novo - - 30500825 Hiatt SM , et al. (2018)
c.73G>A p.Val25Met missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.469T>G p.Ser157Ala missense_variant De novo - Simplex 30500825 Hiatt SM , et al. (2018)
c.-38+8205_-38+8207del - inframe_deletion De novo - Simplex 30500825 Hiatt SM , et al. (2018)
c.73G>A p.Val25Met missense_variant De novo - Simplex 33875846 Bertoli-Avella AM et al. (2021)
c.73G>A p.Val25Met missense_variant De novo - Multi-generational 30500825 Hiatt SM , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Hiatt et al., 2018 described a cohort of ten cases with de novo protein-altering variants in the RALA gene presenting with a neurodevelopmental disorder characterized by developmental delay/intellectual disability, delayed or absent speech, hypotonia, inability to walk, facial dysmorphism, short stature, decreased body weight, and abnormal brain MRI; 3/3 individuals in this cohort for whom information was available also presented with ASD. The same de novo missense variant that was observed in all three ASD cases in Hiatt et al., 2018 (c.73G>A;p.Val25Met) was also observed in a Japanese patient diagnosed with autism spectrum disorder and presenting with a Noonan syndrome-like phenotype in Okamoto et al., 2019.

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
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."

4/1/2021
S
icon
S

Score remained at S

Description

Hiatt et al., 2018 described a cohort of ten cases with de novo protein-altering variants in the RALA gene presenting with a neurodevelopmental disorder characterized by developmental delay/intellectual disability, delayed or absent speech, hypotonia, inability to walk, facial dysmorphism, short stature, decreased body weight, and abnormal brain MRI; 3/3 individuals in this cohort for whom information was available also presented with ASD. The same de novo missense variant that was observed in all three ASD cases in Hiatt et al., 2018 (c.73G>A;p.Val25Met) was also observed in a Japanese patient diagnosed with autism spectrum disorder and presenting with a Noonan syndrome-like phenotype in Okamoto et al., 2019.

Reports Added
[Combining exome/genome sequencing with data repository analysis reveals novel gene-disease associations for a wide range of genetic disorders2021]
10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Hiatt et al., 2018 described a cohort of ten cases with de novo protein-altering variants in the RALA gene presenting with a neurodevelopmental disorder characterized by developmental delay/intellectual disability, delayed or absent speech, hypotonia, inability to walk, facial dysmorphism, short stature, decreased body weight, and abnormal brain MRI; 3/3 individuals in this cohort for whom information was available also presented with ASD. The same de novo missense variant that was observed in all three ASD cases in Hiatt et al., 2018 (c.73G>A;p.Val25Met) was also observed in a Japanese patient diagnosed with autism spectrum disorder and presenting with a Noonan syndrome-like phenotype in Okamoto et al., 2019.

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.49153772414162

Ranking 5445/25841 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 0.95037243142188

Ranking 2676/18225 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 0.90837843911982

Ranking 7318/18665 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 -0.29990647122791

Ranking 17205/20870 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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