Human Gene Module / Chromosome 12 / HECTD4

HECTD4HECT domain E3 ubiquitin protein ligase 4

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
8 / 10
Rare Variants / Common Variants
27 / 0
Aliases
HECTD4, C12orf51,  POTAGE
Associated Syndromes
-
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.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to HECTD4 (10 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 -
5 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
6 Support Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use Husson T , et al. (2020) Yes -
7 Support - Mitani T et al. (2021) No -
8 Support - Mahjani B et al. (2021) Yes -
9 Support - Zhou X et al. (2022) Yes -
10 Recent Recommendation - Faqeih EA et al. (2022) No ASD, stereotypy
Rare Variants   (27)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.9660C>A p.Ala3220%3D stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.8011G>T p.Glu2671Ter stop_gained De novo - - 28714951 Lim ET , et al. (2017)
- p.Ser2668Ter stop_gained Unknown - Simplex 28263302 C Yuen RK et al. (2017)
c.2876T>A p.Leu959Ter stop_gained Unknown - - 34615535 Mahjani B et al. (2021)
c.3523C>G p.Arg1175Gly missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.8443G>T p.Glu2815Ter stop_gained De novo - Simplex 35982159 Zhou X et al. (2022)
c.11062C>T p.Gln3688Ter stop_gained De novo - - 25363760 De Rubeis S , et al. (2014)
c.4389+44C>T - intron_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.6835-20C>G - intron_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.5990T>A p.Met1997Lys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.12743G>A p.Arg4248His missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.12524C>T p.Ala4175Val missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.8676G>A p.Leu2892%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.6824C>G p.Thr2275Arg missense_variant Familial - Simplex 36401616 Faqeih EA et al. (2022)
- p.Pro1010fs frameshift_variant Familial Paternal Simplex 28263302 C Yuen RK et al. (2017)
c.9322+1dup - frameshift_variant Familial Maternal Simplex 32094338 Husson T , et al. (2020)
c.10249C>T p.His3417Tyr missense_variant Familial - Simplex 36401616 Faqeih EA et al. (2022)
c.5449C>T p.Leu1817Phe missense_variant Familial - Multiplex 36401616 Faqeih EA et al. (2022)
c.11992G>A p.Val3998Met missense_variant Familial - Multiplex 36401616 Faqeih EA et al. (2022)
c.4604C>A p.Ala1535Asp missense_variant Unknown - Simplex 31038196 Callaghan DB , et al. (2019)
c.1741C>G p.Gln581Glu missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.2230C>T p.Arg744Ter stop_gained Familial Both parents Simplex 34582790 Mitani T et al. (2021)
c.5965C>T p.Gln1989Ter stop_gained Familial Both parents Multiplex 36401616 Faqeih EA et al. (2022)
c.11540_11542del p.Phe3847del inframe_deletion De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.11651-29T>G - non_coding_transcript_exon_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.5712_5713insC p.Glu1905ArgfsTer31 frameshift_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.4541del p.Pro1514GlnfsTer11 frameshift_variant Familial Both parents Simplex 36401616 Faqeih EA et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

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.

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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
2
icon
1

Decreased from 2 to 1

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.

1/1/2020
2
icon
2

Decreased from 2 to 2

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.

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020] [Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use.2020]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
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.

Reports Added
[New Scoring Scheme]
4/1/2019
3
icon
3

Decreased from 3 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.

Reports Added
[Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort.2019]
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.
Original Source
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
Original Source
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
Original Source
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).
Original Source
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