Human Gene Module / Chromosome 14 / TRAPPC6B

TRAPPC6Btrafficking protein particle complex 6B

Score
S
Syndromic Syndromic
Autism Reports / Total Reports
0 / 4
Rare Variants / Common Variants
5 / 0
Aliases
TRAPPC6B, TPC6
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
14q21.1
Associated Disorders
ASD
Relevance to Autism

A homozygous founder splice-site variant in the TRAPPC6B gene was identified in six individuals from three unrelated Egyptian families presenting with a neurodevelopmental disorder characterized by autistic features (poor social interaction and motor stereotypies such as hand flapping), motor delay, delayed or absent speech, epilepsy, and microcephaly (Marin-Valencia et al., 2017). In the same report, zebrafish trappc6b morphants were found to exhibit reduced head size and lowered seizure threshold, thereby replicating the human phenotype. A homozygous nonsense variant in the TRAPPC6B gene had previously been identified in a consanguineous family with two individuals presenting with autosomal-recessive intellectual disability (Harripaul et al., 2017).

Molecular Function

TRAPPC6B is a component of TRAPP complexes, which are tethering complexes involved in vesicle transport. It may play a role in vesicular transport from endoplasmic reticulum to Golgi.

Reports related to TRAPPC6B (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguin... Harripaul R , et al. (2017) No -
2 Primary A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features. Marin-Valencia I , et al. (2017) No Autistic features (poor social interaction, motor
3 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. Monies D , et al. (2019) No ASD
4 Support Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing. Bruel AL , et al. (2019) No -
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.91C>T p.Arg31Ter stop_gained Unknown Both parents - 31231135 Bruel AL , et al. (2019)
c.381_382del p.Gly128TrpfsTer14 splice_site_variant - Both parents - 31130284 Monies D , et al. (2019)
c.124C>T p.Arg42Ter stop_gained Familial Both parents Multiplex 28397838 Harripaul R , et al. (2017)
c.82-2A>G - splice_site_variant Familial Both parents Multiplex 28626029 Marin-Valencia I , et al. (2017)
c.416del p.Val139GlufsTer15 frameshift_variant Familial Both parents Not simplex (positive family history) 31130284 Monies D , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

A homozygous founder splice-site variant in the TRAPPC6B gene was identified in six individuals from three unrelated Egyptian families presenting with a neurodevelopmental disorder characterized by autistic features (poor social interaction and motor stereotypies such as hand flapping), motor delay, delayed or absent speech, epilepsy, and microcephaly (Marin-Valencia et al., 2017). In the same report, zebrafish trappc6b morphants were found to exhibit reduced head size and lowered seizure threshold, thereby replicating the human phenotype. A homozygous nonsense variant in the TRAPPC6B gene had previously been identified in a consanguineous family with two individuals presenting with autosomal-recessive intellectual disability (Harripaul et al., 2017).

Score Delta: Score remained at S

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."

10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

A homozygous founder splice-site variant in the TRAPPC6B gene was identified in six individuals from three unrelated Egyptian families presenting with a neurodevelopmental disorder characterized by autistic features (poor social interaction and motor stereotypies such as hand flapping), motor delay, delayed or absent speech, epilepsy, and microcephaly (Marin-Valencia et al., 2017). In the same report, zebrafish trappc6b morphants were found to exhibit reduced head size and lowered seizure threshold, thereby replicating the human phenotype. A homozygous nonsense variant in the TRAPPC6B gene had previously been identified in a consanguineous family with two individuals presenting with autosomal-recessive intellectual disability (Harripaul et al., 2017).

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

Score remained at S

Description

A homozygous founder splice-site variant in the TRAPPC6B gene was identified in six individuals from three unrelated Egyptian families presenting with a neurodevelopmental disorder characterized by autistic features (poor social interaction and motor stereotypies such as hand flapping), motor delay, delayed or absent speech, epilepsy, and microcephaly (Marin-Valencia et al., 2017). In the same report, zebrafish trappc6b morphants were found to exhibit reduced head size and lowered seizure threshold, thereby replicating the human phenotype. A homozygous nonsense variant in the TRAPPC6B gene had previously been identified in a consanguineous family with two individuals presenting with autosomal-recessive intellectual disability (Harripaul et al., 2017).

Krishnan Probability Score

Score 0.41992685868384

Ranking 21168/25841 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.
ExAC Score

Score 0.021980277629556

Ranking 9319/18225 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
Sanders TADA Score

Score 0.92776195545174

Ranking 10749/18665 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).
Zhang D Score

Score -0.2623684729846

Ranking 16602/20870 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.
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SFARI Gene Update

We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
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