Human Gene Module / Chromosome 1 / TMEM39B

TMEM39Btransmembrane protein 39B

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 5
Rare Variants / Common Variants
4 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
1p35.2
Associated Disorders
-
Relevance to Autism

A de novo missense variant in the TMEM39B gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014, a de novo frameshift variant in this gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014., and a maternally-transmitted frameshift variant in this gene was identified in one of two affected siblings from a multiplex ASD family from the iHART cohort (Ruzzo et al., 2019). Two separate studies used TADA analysis to identify TMEM39B as an ASD candidate gene with a q-value < 0.1 (Du et al., 2019; Ruzzo et al., 2019).

Molecular Function

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TMEM39B (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Recent Recommendation Nonrandom occurrence of multiple de novo coding variants in a proband indicates the existence of an oligogenic model in autism Du Y , et al. (2019) Yes -
4 Recent Recommendation Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
5 Support - Costa CIS et al. (2023) Yes -
Rare Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.529C>T p.Arg177Ter stop_gained De novo - Simplex 25363768 Iossifov I et al. (2014)
c.835A>G p.Lys279Glu missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.353C>T p.Thr118Met missense_variant De novo - Simplex 37280359 Costa CIS et al. (2023)
c.-26del - frameshift_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo missense variant in the TMEM39B gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014, a de novo frameshift variant in this gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014., and a maternally-transmitted frameshift variant in this gene was identified in one of two affected siblings from a multiplex ASD family from the iHART cohort (Ruzzo et al., 2019). Two separate studies used TADA analysis to identify TMEM39B as an ASD candidate gene with a q-value < 0.1 (Du et al., 2019; Ruzzo et al., 2019).

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 de novo missense variant in the TMEM39B gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014, a de novo frameshift variant in this gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014., and a maternally-transmitted frameshift variant in this gene was identified in one of two affected siblings from a multiplex ASD family from the iHART cohort (Ruzzo et al., 2019). Two separate studies used TADA analysis to identify TMEM39B as an ASD candidate gene with a q-value < 0.1 (Du et al., 2019; Ruzzo et al., 2019).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A de novo missense variant in the TMEM39B gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014, a de novo frameshift variant in this gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014., and a maternally-transmitted frameshift variant in this gene was identified in one of two affected siblings from a multiplex ASD family from the iHART cohort (Ruzzo et al., 2019). Two separate studies used TADA analysis to identify TMEM39B as an ASD candidate gene with a q-value < 0.1 (Du et al., 2019; Ruzzo et al., 2019).

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

Increased from to 4

Description

A de novo missense variant in the TMEM39B gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014, a de novo frameshift variant in this gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014., and a maternally-transmitted frameshift variant in this gene was identified in one of two affected siblings from a multiplex ASD family from the iHART cohort (Ruzzo et al., 2019). Two separate studies used TADA analysis to identify TMEM39B as an ASD candidate gene with a q-value < 0.1 (Du et al., 2019; Ruzzo et al., 2019).

Krishnan Probability Score

Score 0.43274540607854

Ranking 20666/25841 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 0.021450432147613

Ranking 9336/18225 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 0.11013944949984

Ranking 69/18665 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 0.099562092908392

Ranking 6148/20870 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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