Human Gene Module / Chromosome 6 / HACE1

HACE1HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
7 / 13
Rare Variants / Common Variants
18 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
6q16.3
Associated Disorders
-
Relevance to Autism

A de novo missense variant in the HACE1 gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; functional assessment of this variant by a high throughput Massively Parallel Splicing Assay (MaPSY) in Rhine et al., 2022 demonstrated that this variant disrupted splicing, and this functional effect was further validated by RT-PCR. A de novo in-frame deletion variant and multiple rare de novo non-coding variants in HACE1 have also been observed in ASD probands (Krumm et al., 2015; Yuen et al., 2017;Turner et al., 2017).

Molecular Function

This gene encodes a HECT domain and ankyrin repeat-containing ubiquitin ligase. The encoded protein is involved in specific tagging of target proteins, leading to their subcellular localization or proteasomal degradation. The protein is a potential tumor suppressor and is involved in the pathophysiology of several tumors, including Wilm's tumor. Biallelic variants in HACE1 are responsible for spastic paraplegia and psychomotor retardation with or without seizures (SPPRS; OMIM 616756), an autosomal recessive complex neurodevelopmental disorder with onset in infancy in which affected children show hypotonia followed by severely impaired global development and significant motor disability (Hollstein et al., 2015; Akawi et al., 2015).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to HACE1 (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
3 Support - Hollstein R et al. (2015) No -
4 Support - Akawi N et al. (2015) No -
5 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
6 Support Genomic Patterns of De Novo Mutation in Simplex Autism Turner TN et al. (2017) Yes -
7 Recent Recommendation - Rhine CL et al. (2022) Yes -
8 Support - Zhou X et al. (2022) Yes -
9 Support - Spataro N et al. (2023) No -
10 Support - Bartolomaeus T et al. (2023) No -
11 Support - Riquin K et al. (2023) No -
12 Support - Sanchis-Juan A et al. (2023) No -
13 Support - Soo-Whee Kim et al. (2024) Yes -
Rare Variants   (18)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.222-22C>T - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.326+2789T>C - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.618-5554A>G - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.2212-7180G>T - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.2381+2029A>G - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.2381+3049dup - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.2344-980C>T - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.403-4954T>G - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.152C>G p.Ser51Ter stop_gained Familial Paternal - 36980980 Spataro N et al. (2023)
c.1420C>T p.Pro474Ser missense_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.1953G>A p.Ala651= synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2242C>T p.Arg748Ter stop_gained Familial Maternal - 36980980 Spataro N et al. (2023)
c.805C>T p.Arg269Ter stop_gained Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.148_150del p.Leu50del inframe_deletion De novo - Simplex 25961944 Krumm N , et al. (2015)
c.1753C>T p.Arg585Trp missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.259_262del p.Lys87GlufsTer27 frameshift_variant Familial - Simplex 37495270 Riquin K et al. (2023)
c.1439_1442del p.Val480AlafsTer7 frameshift_variant Familial - Simplex 37495270 Riquin K et al. (2023)
c.402+5G>A - splice_site_variant Familial Both parents Multiplex 37460657 Bartolomaeus T et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Functional assessment of ASD-associated variant

Score Delta: Score remained at 3

criteria met
See SFARI Gene'scoring criteria
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.

4/1/2022
icon
3

Increased from to 3

Description

Functional assessment of ASD-associated variant

Krishnan Probability Score

Score 0.45879582008744

Ranking 9642/25841 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 0.0015956625244719

Ranking 11443/18225 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 0.85722465857986

Ranking 3735/18665 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 0.50435012070087

Ranking 493/20870 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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