Human Gene Module / Chromosome X / RAB39B

RAB39BRAB39B, member RAS oncogene family

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
10 / 19
Rare Variants / Common Variants
17 / 0
Aliases
RAB39B, RP13-228J13.2,  MRX72
Associated Syndromes
-
Chromosome Band
Xq28
Associated Disorders
SCZ, ASD, EPS, ID
Relevance to Autism

Rare mutations in the RAB39B gene have been identified with autism (Giannandrea et al., 2010).

Molecular Function

This gene encodes a member of the Rab family of proteins. Rab proteins are small GTPases that are involved in vesicular trafficking.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to RAB39B (19 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Isolation and characterization of a human novel RAB (RAB39B) gene Cheng H , et al. (2002) No -
2 Recent Recommendation Gene expression profiling identifies new biological markers of neoplastic germ cells Biermann K , et al. (2007) No -
3 Primary Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly Giannandrea M , et al. (2010) Yes X-linked MR, epilepsy
4 Support A de novo paradigm for mental retardation Vissers LE , et al. (2010) No -
5 Recent Recommendation Increased dosage of RAB39B affects neuronal development and could explain the cognitive impairment in male patients with distal Xq28 copy number gains Vanmarsenille L , et al. (2013) No SCZ
6 Recent Recommendation Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with ?-synuclein pathology Wilson GR , et al. (2014) No -
7 Support Whole-genome sequencing of quartet families with autism spectrum disorder Yuen RK , et al. (2015) Yes -
8 Recent Recommendation The intellectual disability protein RAB39B selectively regulates GluA2 trafficking to determine synaptic AMPAR composition Mignogna ML , et al. (2015) No -
9 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
10 Support Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly Woodbury-Smith M , et al. (2017) Yes Macrocephaly
11 Support The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children Long S , et al. (2019) Yes -
12 Support Characterization of intellectual disability and autism comorbidity through gene panel sequencing Aspromonte MC , et al. (2019) Yes -
13 Support Cerebral organoid and mouse models reveal a RAB39b-PI3K-mTOR pathway-dependent dysregulation of cortical development leading to macrocephaly/autism phenotypes Zhang W et al. (2020) No -
14 Support A novel RAB39B mutation and concurrent de novo NF1 mutation in a boy with neurofibromatosis type 1, intellectual disability, and autism: a case report Santoro C et al. (2020) No ASD, ID, epilepsy/seizures
15 Support - Mignogna ML et al. (2021) Yes -
16 Support - Hu C et al. (2022) Yes -
17 Support - Zhou X et al. (2022) Yes -
18 Support - Wang Z et al. (2023) No -
19 Support - Sheth F et al. (2023) Yes DD, ID, epilepsy/seizures
Rare Variants   (17)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.43G>C p.Gly15Arg missense_variant Unknown - - 35741772 Hu C et al. (2022)
c.331G>A p.Val111Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Maternal Multiplex 25434005 Wilson GR , et al. (2014)
c.31C>T p.Leu11Phe missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.557G>A p.Trp186Ter stop_gained De novo - Simplex 21076407 Vissers LE , et al. (2010)
- - copy_number_gain Familial Maternal Simplex 24357492 Vanmarsenille L , et al. (2013)
c.431C>T p.Ala144Val missense_variant Unknown - Simplex 37543562 Sheth F et al. (2023)
- - copy_number_gain Familial Maternal Multiplex 24357492 Vanmarsenille L , et al. (2013)
c.473T>C p.Ile158Thr missense_variant Familial Maternal - 31139143 Long S , et al. (2019)
c.559G>T p.Glu187Ter stop_gained Familial Maternal Multiplex 25621899 Yuen RK , et al. (2015)
- - copy_number_gain Unknown Mother not tested Simplex 24357492 Vanmarsenille L , et al. (2013)
c.640T>C p.Ter214GlnextTer21 stop_lost Familial Maternal Multiplex 34761259 Mignogna ML et al. (2021)
c.21C>A p.Tyr7Ter stop_gained Familial Maternal Multi-generational 20159109 Giannandrea M , et al. (2010)
c.215+1G>A - splice_site_variant Familial Maternal Multi-generational 20159109 Giannandrea M , et al. (2010)
c.503C>A p.Thr168Lys missense_variant Familial Maternal Extended multiplex 25434005 Wilson GR , et al. (2014)
c.579T>G p.Phe193Leu missense_variant Familial Maternal Multi-generational 31209962 Aspromonte MC , et al. (2019)
c.436_447del p.Gly146_Tyr149del inframe_deletion Familial Maternal Extended multiplex 32873259 Santoro C et al. (2020)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A paper by Giannandrea et al. (2010) reports mutations that segregate with intellectual disability in families, and in some family members (one per large family) intellectual disability is associated with autism spectrum disorder, epileptic seizures, and macrocephaly. In the first of two families studied, 2/6 males with ID present with ASD; in the second family, 1 of 8 with ID present with ASD. Although mutations appear to segregate well with ID, only 1/13 individuals (two large families) has autism.

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

A paper by Giannandrea et al. (2010) reports mutations that segregate with intellectual disability in families, and in some family members (one per large family) intellectual disability is associated with autism spectrum disorder, epileptic seizures, and macrocephaly. In the first of two families studied, 2/6 males with ID present with ASD; in the second family, 1 of 8 with ID present with ASD. Although mutations appear to segregate well with ID, only 1/13 individuals (two large families) has autism.

7/1/2020
3
icon
3

Decreased from 3 to 3

Description

A paper by Giannandrea et al. (2010) reports mutations that segregate with intellectual disability in families, and in some family members (one per large family) intellectual disability is associated with autism spectrum disorder, epileptic seizures, and macrocephaly. In the first of two families studied, 2/6 males with ID present with ASD; in the second family, 1 of 8 with ID present with ASD. Although mutations appear to segregate well with ID, only 1/13 individuals (two large families) has autism.

Reports Added
[A novel RAB39B mutation and concurrent de novo NF1 mutation in a boy with neurofibromatosis type 1, intellectual disability, and autism: a case report2020]
1/1/2020
3
icon
3

Decreased from 3 to 3

Description

A paper by Giannandrea et al. (2010) reports mutations that segregate with intellectual disability in families, and in some family members (one per large family) intellectual disability is associated with autism spectrum disorder, epileptic seizures, and macrocephaly. In the first of two families studied, 2/6 males with ID present with ASD; in the second family, 1 of 8 with ID present with ASD. Although mutations appear to segregate well with ID, only 1/13 individuals (two large families) has autism.

Reports Added
[Cerebral organoid and mouse models reveal a RAB39b-PI3K-mTOR pathway-dependent dysregulation of cortical development leading to macrocephaly/autism phenotypes2020]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A paper by Giannandrea et al. (2010) reports mutations that segregate with intellectual disability in families, and in some family members (one per large family) intellectual disability is associated with autism spectrum disorder, epileptic seizures, and macrocephaly. In the first of two families studied, 2/6 males with ID present with ASD; in the second family, 1 of 8 with ID present with ASD. Although mutations appear to segregate well with ID, only 1/13 individuals (two large families) has autism.

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

A paper by Giannandrea et al. (2010) reports mutations that segregate with intellectual disability in families, and in some family members (one per large family) intellectual disability is associated with autism spectrum disorder, epileptic seizures, and macrocephaly. In the first of two families studied, 2/6 males with ID present with ASD; in the second family, 1 of 8 with ID present with ASD. Although mutations appear to segregate well with ID, only 1/13 individuals (two large families) has autism.

Reports Added
[The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children.2019] [Characterization of intellectual disability and autism comorbidity through gene panel sequencing.2019]
10/1/2017
4
icon
4

Decreased from 4 to 4

Description

A paper by Giannandrea et al. (2010) reports mutations that segregate with intellectual disability in families, and in some family members (one per large family) intellectual disability is associated with autism spectrum disorder, epileptic seizures, and macrocephaly. In the first of two families studied, 2/6 males with ID present with ASD; in the second family, 1 of 8 with ID present with ASD. Although mutations appear to segregate well with ID, only 1/13 individuals (two large families) has autism.

Reports Added
[Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.2017] [Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly.2017]
4/1/2017
4
icon
4

Decreased from 4 to 4

Description

A paper by Giannandrea et al. (2010) reports mutations that segregate with intellectual disability in families, and in some family members (one per large family) intellectual disability is associated with autism spectrum disorder, epileptic seizures, and macrocephaly. In the first of two families studied, 2/6 males with ID present with ASD; in the second family, 1 of 8 with ID present with ASD. Although mutations appear to segregate well with ID, only 1/13 individuals (two large families) has autism.

Reports Added
[Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly.2010] [Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [A de novo paradigm for mental retardation.2010] [Increased dosage of RAB39B affects neuronal development and could explain the cognitive impairment in male patients with distal Xq28 copy number ga...2013] [Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with -synuclein pathology.2014] [Isolation and characterization of a human novel RAB (RAB39B) gene.2002] [Gene expression profiling identifies new biological markers of neoplastic germ cells.2007] [The intellectual disability protein RAB39B selectively regulates GluA2 trafficking to determine synaptic AMPAR composition.2015]
4/1/2015
4
icon
4

Decreased from 4 to 4

Description

A paper by Giannandrea et al. (2010) reports mutations that segregate with intellectual disability in families, and in some family members (one per large family) intellectual disability is associated with autism spectrum disorder, epileptic seizures, and macrocephaly. In the first of two families studied, 2/6 males with ID present with ASD; in the second family, 1 of 8 with ID present with ASD. Although mutations appear to segregate well with ID, only 1/13 individuals (two large families) has autism.

Reports Added
[The intellectual disability protein RAB39B selectively regulates GluA2 trafficking to determine synaptic AMPAR composition.2015]
1/1/2015
4
icon
4

Decreased from 4 to 4

Description

A paper by Giannandrea et al. (2010) reports mutations that segregate with intellectual disability in families, and in some family members (one per large family) intellectual disability is associated with autism spectrum disorder, epileptic seizures, and macrocephaly. In the first of two families studied, 2/6 males with ID present with ASD; in the second family, 1 of 8 with ID present with ASD. Although mutations appear to segregate well with ID, only 1/13 individuals (two large families) has autism.

Reports Added
[Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with -synuclein pathology.2014]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

A paper by Giannandrea et al. (2010) reports mutations that segregate with intellectual disability in families, and in some family members (one per large family) intellectual disability is associated with autism spectrum disorder, epileptic seizures, and macrocephaly. In the first of two families studied, 2/6 males with ID present with ASD; in the second family, 1 of 8 with ID present with ASD. Although mutations appear to segregate well with ID, only 1/13 individuals (two large families) has autism.

4/1/2014
No data
icon
4

Increased from No data to 4

Description

A paper by Giannandrea et al. (2010) reports mutations that segregate with intellectual disability in families, and in some family members (one per large family) intellectual disability is associated with autism spectrum disorder, epileptic seizures, and macrocephaly. In the first of two families studied, 2/6 males with ID present with ASD; in the second family, 1 of 8 with ID present with ASD. Although mutations appear to segregate well with ID, only 1/13 individuals (two large families) has autism.

Krishnan Probability Score

Score 0.49817429709136

Ranking 2283/25841 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 0.71519629704231

Ranking 4400/18225 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 0.90703081850812

Ranking 7151/18665 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
Larsen Cumulative Evidence Score

Score 8

Ranking 232/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score -0.18574769644623

Ranking 15102/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
ALPI Intestinal-type alkaline phosphatase Human Protein Binding 248 P09923
KLK8 Kallikrein-8 Human Protein Binding 11202 O60259-2
LAMP3 Lysosome-associated membrane glycoprotein 3 Human Protein Binding 27074 Q9UQV4
PMEL Melanocyte protein PMEL Human Protein Binding 6490 P40967-2
SLC15A1 Solute carrier family 15 member 1 Human Protein Binding 6564 P46059
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