Human Gene Module / Chromosome 12 / HECTD4

HECTD4HECT domain E3 ubiquitin protein ligase 4

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
4 / 4
Rare Variants / Common Variants
7 / 0
Aliases
HECTD4, C12orf51,  POTAGE
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
12q24.13
Associated Disorders
-
Relevance to Autism

Two de novo variants in the HECTD4 gene (one nonsense, one missense) were identified in ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014. Yuen et al., 2017 identified additional HECTD4 loss-of-function variants by whole genome sequencing in three ASD families. Despite being a mutation-intolerant gene with a pLI score of 1.00, HECTD4 did not meet the statistical significance criteria used in Yuen et al., 2017 to be designated as an ASD candidate gene, which was a higher-than-expected mutation rate (false discovery rate < 15%).

Molecular Function

E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.

Reports related to HECTD4 (4 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 Recent Recommendation Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
3 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Lim ET , et al. (2017) Yes -
4 Support Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort. Callaghan DB , et al. (2019) Yes -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
C>A p.Glu2659Ter stop_gained De novo - - 28714951 Lim ET , et al. (2017)
- p.Ser2668Ter stop_gained Unknown - Simplex 28263302 C Yuen RK , et al. (2017)
c.11062C>T p.Gln3688Ter stop_gained De novo - - 25363760 De Rubeis S , et al. (2014)
c.12743G>A p.Arg4248His missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
G>T p.Ala1535Asp missense_variant Unknown - Simplex 31038196 Callaghan DB , et al. (2019)
insG p.Pro1904fs frameshift_variant De novo - Multiplex 28263302 C Yuen RK , et al. (2017)
- p.Pro1010fs frameshift_variant Familial Paternal Simplex 28263302 C Yuen RK , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

3

Score Delta: Score remained at 3.3

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

7/1/2017
4
icon
3

Decreased from 4 to 3

Description

Two de novo variants in the HECTD4 gene (one nonsense, one missense) were identified in ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014. Yuen et al., 2017 identified additional HECTD4 loss-of-function variants by whole genome sequencing in three ASD families. Despite being a mutation-intolerant gene with a pLI score of 1.00, HECTD4 did not meet the statistical significance criteria used in Yuen et al., 2017 to be designated as an ASD candidate gene, which was a higher-than-expected mutation rate (false discovery rate < 15%). A de novo postzygotic mosaic nonsense variant in the HECTD4 gene was identified in a female ASD proband in Lim et al., 2017.

4/1/2017
icon
4

Increased from to 4

Description

Two de novo variants in the HECTD4 gene (one nonsense, one missense) were identified in ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014. Yuen et al., 2017 identified additional HECTD4 loss-of-function variants by whole genome sequencing in three ASD families. Despite being a mutation-intolerant gene with a pLI score of 1.00, HECTD4 did not meet the statistical significance criteria used in Yuen et al., 2017 to be designated as an ASD candidate gene, which was a higher-than-expected mutation rate (false discovery rate < 15%).

Krishnan Probability Score

Score 0.49439107041108

Ranking 3687/25841 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 0.99999999999996

Ranking 23/18225 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
Iossifov Probability Score

Score 0.964

Ranking 69/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.92251644775251

Ranking 9589/18665 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).
CNVs associated with HECTD4(1 CNVs)
12q24.13 6 Deletion 14  /  21
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