Human Gene Module / Chromosome 9 / ZNF462

ZNF462Zinc finger protein 462

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
9 / 16
Rare Variants / Common Variants
38 / 0
EAGLE Score
10.6
Moderate Learn More
Aliases
ZNF462, Zfp462
Associated Syndromes
Weiss-Kruszka syndrome, ID, Weiss-Kruszka syndrome, DD, ID
Chromosome Band
9q31.2
Associated Disorders
ID, ASD, EPS
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance to Autism

Three de novo variants in the ZNF462 gene (one frameshift, two missense) have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=4.03 x 10-3) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015). Weiss et al., 2017 reported eight subjects from six families with predicted loss of function variants in ZNF462 and overlapping phenotypes including developmental delay, ptosis, metopic ridging, craniosynostosis, and dysgenesis of the corpus callosum; two of the subjects identified in this report were additionally diagnosed with ASD, while another subject exhibited autistic features (hand flapping and inability to demonstrate joint attention or reciprocal play).

Molecular Function

The protein encoded by this gene may be involved in transcriptional regulation (by similarity).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ZNF462 (16 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 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
4 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
5 Recent Recommendation Haploinsufficiency of ZNF462 is associated with craniofacial anomalies, corpus callosum dysgenesis, ptosis, and developmental delay Weiss K , et al. (2017) No ASD or autistic features
6 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) Yes -
7 Support ZNF462 and KLF12 are disrupted by a de novo translocation in a patient with syndromic intellectual disability and autism spectrum disorder Cosemans N , et al. (2018) Yes -
8 Support Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort Callaghan DB , et al. (2019) Yes -
9 Support Phenotype delineation of ZNF462 related syndrome Kruszka P , et al. (2019) No ASD
10 Support - Bertoli-Avella AM et al. (2021) No ID, epilepsy/seizures
11 Support - Zhou X et al. (2022) Yes -
12 Support - Yelagandula R et al. (2023) No -
13 Support - Erica Rosina et al. (2024) No -
14 Support - Axel Schmidt et al. (2024) No -
15 Support - Liselot van der Laan et al. (2024) No ASD, ADHD
16 Support - Suhua Chang et al. () Yes -
Rare Variants   (38)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - Simplex 28513610 Weiss K , et al. (2017)
- - translocation De novo - Simplex 29427787 Cosemans N , et al. (2018)
c.466G>T p.Glu156Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.7057-2A>G - splice_site_variant De novo - - 31361404 Kruszka P , et al. (2019)
c.2804C>T p.Pro935Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4165C>T p.Gln1389Ter stop_gained De novo - - 31361404 Kruszka P , et al. (2019)
c.6619A>G p.Arg2207Gly missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.7266G>A p.Ala2422%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.3252+1011del - frameshift_variant De novo - Simplex 28513610 Weiss K , et al. (2017)
c.3253-1468del - frameshift_variant De novo - Simplex 28513610 Weiss K , et al. (2017)
c.5680T>G p.Cys1894Gly missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.434C>T p.Pro145Leu missense_variant De novo - Simplex 39126614 Suhua Chang et al. ()
c.2590C>T p.Arg864Ter stop_gained Familial Maternal - 31361404 Kruszka P , et al. (2019)
c.3253-1215G>A - missense_variant Unknown - Simplex 31038196 Callaghan DB , et al. (2019)
c.6124C>A p.Arg2042Ser missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.5426C>T p.Ala1809Val missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.2695G>T p.Glu899Ter stop_gained Unknown Not maternal - 31361404 Kruszka P , et al. (2019)
c.2075_2077del p.Lys692del inframe_deletion De novo - Simplex 35982159 Zhou X et al. (2022)
c.882dup p.Ser295GlnfsTer64 frameshift_variant De novo - - 31361404 Kruszka P , et al. (2019)
c.5848C>A p.Pro1950Thr missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2049dup p.Pro684SerfsTer14 frameshift_variant De novo - - 31361404 Kruszka P , et al. (2019)
c.2542del p.Cys848ValfsTer66 frameshift_variant De novo - - 31361404 Kruszka P , et al. (2019)
c.3854del p.Pro1285GlnfsTer7 frameshift_variant De novo - - 31361404 Kruszka P , et al. (2019)
c.1234_1235insAA p.Ser412Ter frameshift_variant Unknown - - 31361404 Kruszka P , et al. (2019)
c.1615C>T p.Gln539Ter stop_gained De novo - Simplex 33875846 Bertoli-Avella AM et al. (2021)
c.1855C>T p.Gln619Ter stop_gained De novo - Simplex 33875846 Bertoli-Avella AM et al. (2021)
c.6174_6175del p.Cys2059LeufsTer7 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.4016dup p.Ser1340GlufsTer28 frameshift_variant De novo - - 31361404 Kruszka P , et al. (2019)
c.763C>T p.Arg255Ter stop_gained Familial Paternal Simplex 31361404 Kruszka P , et al. (2019)
c.3787C>T p.Arg1263Ter stop_gained Familial Paternal Multiplex 28513610 Weiss K , et al. (2017)
c.831_834del p.Arg277SerfsTer26 frameshift_variant De novo - - 31361404 Kruszka P , et al. (2019)
c.3111dup p.Ala1038CysfsTer25 frameshift_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.3436_3437del p.Arg1146GlufsTer41 frameshift_variant De novo - - 31361404 Kruszka P , et al. (2019)
c.4792A>T p.Lys1598Ter stop_gained Unknown - Multiplex 39069253 Liselot van der Laan et al. (2024)
c.3549del p.His1183GlnfsTer22 frameshift_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.2253_2254dup p.Pro752LeufsTer12 frameshift_variant De novo - Simplex 38041506 Erica Rosina et al. (2024)
c.2979_2980delinsA p.Val994TrpfsTer147 frameshift_variant De novo - Simplex 28513610 Weiss K , et al. (2017)
c.3078dup p.Val1027CysfsTer5 frameshift_variant De novo - Simplex 39069253 Liselot van der Laan et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

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.

S

Syndromic

See all Category S Genes

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."

4/1/2021
1
icon
1

Score remained at 1

Description

Three de novo variants in the ZNF462 gene (one frameshift, two missense) have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=4.03 x 10-3) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015). Weiss et al., 2017 reported eight subjects from six families with predicted loss of function variants in ZNF462 and overlapping phenotypes including developmental delay, ptosis, metopic ridging, craniosynostosis, and dysgenesis of the corpus callosum; two of the subjects identified in this report were additionally diagnosed with ASD, while another subject exhibited autistic features (hand flapping and inability to demonstrate joint attention or reciprocal play). Kruszka et al., 2019 presented 14 novel individuals with loss-of-function variants in the ZNF462 gene, two of whom presented with autism spectrum disorder.

Reports Added
[Combining exome/genome sequencing with data repository analysis reveals novel gene-disease associations for a wide range of genetic disorders2021]
10/1/2019
4S
icon
1

Decreased from 4S to 1

New Scoring Scheme
Description

Three de novo variants in the ZNF462 gene (one frameshift, two missense) have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=4.03 x 10-3) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015). Weiss et al., 2017 reported eight subjects from six families with predicted loss of function variants in ZNF462 and overlapping phenotypes including developmental delay, ptosis, metopic ridging, craniosynostosis, and dysgenesis of the corpus callosum; two of the subjects identified in this report were additionally diagnosed with ASD, while another subject exhibited autistic features (hand flapping and inability to demonstrate joint attention or reciprocal play). Kruszka et al., 2019 presented 14 novel individuals with loss-of-function variants in the ZNF462 gene, two of whom presented with autism spectrum disorder.

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

Decreased from 4S to 4S

Description

Three de novo variants in the ZNF462 gene (one frameshift, two missense) have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=4.03 x 10-3) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015). Weiss et al., 2017 reported eight subjects from six families with predicted loss of function variants in ZNF462 and overlapping phenotypes including developmental delay, ptosis, metopic ridging, craniosynostosis, and dysgenesis of the corpus callosum; two of the subjects identified in this report were additionally diagnosed with ASD, while another subject exhibited autistic features (hand flapping and inability to demonstrate joint attention or reciprocal play). Kruszka et al., 2019 presented 14 novel individuals with loss-of-function variants in the ZNF462 gene, two of whom presented with autism spectrum disorder.

Reports Added
[Phenotype delineation of ZNF462 related syndrome.2019]
4/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

Three de novo variants in the ZNF462 gene (one frameshift, two missense) have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=4.03 x 10-3) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015). Weiss et al., 2017 reported eight subjects from six families with predicted loss of function variants in ZNF462 and overlapping phenotypes including developmental delay, ptosis, metopic ridging, craniosynostosis, and dysgenesis of the corpus callosum; two of the subjects identified in this report were additionally diagnosed with ASD, while another subject exhibited autistic features (hand flapping and inability to demonstrate joint attention or reciprocal play).

Reports Added
[Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort.2019]
4/1/2017
icon
4S

Increased from to 4S

Description

Three de novo variants in the ZNF462 gene (one frameshift, two missense) have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=4.03 x 10-3) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015). Weiss et al., 2017 reported eight subjects from six families with predicted loss of function variants in ZNF462 and overlapping phenotypes including developmental delay, ptosis, metopic ridging, craniosynostosis, and dysgenesis of the corpus callosum; two of the subjects identified in this report were additionally diagnosed with ASD, while another subject exhibited autistic features (hand flapping and inability to demonstrate joint attention or reciprocal play).

Reports Added
[Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Excess of rare, inherited truncating mutations in autism.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Haploinsufficiency of ZNF462 is associated with craniofacial anomalies, corpus callosum dysgenesis, ptosis, and developmental delay.2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
Krishnan Probability Score

Score 0.49386062083278

Ranking 3948/25841 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 0.9999999984001

Ranking 108/18225 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 0.984

Ranking 39/239 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 0.80472618874794

Ranking 2293/18665 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 0.32065936482321

Ranking 2424/20870 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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