Human Gene Module / Chromosome 19 / ZC3H4

ZC3H4zinc finger CCCH-type containing 4

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 4
Rare Variants / Common Variants
20 / 0
Aliases
ZC3H4, C19orf7
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
19q13.32
Associated Disorders
-
Relevance to Autism

Two de novo frameshift variants in the ZC3H4 gene were identified in the same ASD proband from the Simons Simplex Collection in Iossifov et al., 2014.

Molecular Function

This gene encodes a member of a family of CCCH (C-x8-C-x5-C-x3-H type) zinc finger domain-containing proteins. These zinc finger domains, which coordinate zinc finger binding and are characterized by three cysteine residues and one histidine residue, are nucleic acid-binding. Other family members are known to function in post-transcriptional regulation.

Reports related to ZC3H4 (4 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 Recent Recommendation Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases Stessman HA , et al. (2017) Yes -
3 Support Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder Krupp DR , et al. (2017) Yes -
4 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
Rare Variants   (20)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.507C>A p.Tyr169Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.332G>A p.Arg111Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.353C>G p.Ser118Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.424G>A p.Asp142Asn missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.458G>A p.Arg153His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.476G>T p.Ser159Ile missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.556G>T p.Asp186Tyr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.619G>A p.Asp207Asn missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.727C>T p.Arg243Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.733C>T p.Arg245Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.757C>T p.Arg253Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.776G>A p.Arg259His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.877G>A p.Glu293Lys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.320G>A p.Arg107Gln missense_variant De novo NA - 33004838 Wang T et al. (2020)
c.2050A>G p.Met684Val missense_variant De novo NA - 33004838 Wang T et al. (2020)
c.319C>T p.Arg107Trp missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.1346A>T p.Lys449Met missense_variant De novo NA Simplex 28867142 Krupp DR , et al. (2017)
c.2164G>A p.Glu722Lys missense_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.1343del p.Cys448LeufsTer23 frameshift_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.1348del p.Leu450CysfsTer21 frameshift_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo frameshift variants in the ZC3H4 gene were identified in the same ASD proband from the Simons Simplex Collection in Iossifov et al., 2014.

Score Delta: Score remained at 3

2

Strong Candidate

See all Category 2 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.

10/1/2020
3
icon
3

Score remained at 3

Description

Two de novo frameshift variants in the ZC3H4 gene were identified in the same ASD proband from the Simons Simplex Collection in Iossifov et al., 2014.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Two de novo frameshift variants in the ZC3H4 gene were identified in the same ASD proband from the Simons Simplex Collection in Iossifov et al., 2014.

Reports Added
[New Scoring Scheme]
10/1/2017
3
icon
3

Decreased from 3 to 3

Description

Two de novo frameshift variants in the ZC3H4 gene were identified in the same ASD proband from the Simons Simplex Collection in Iossifov et al., 2014.

1/1/2017
icon
3

Increased from to 3

Description

Two de novo frameshift variants in the ZC3H4 gene were identified in the same ASD proband from the Simons Simplex Collection in Iossifov et al., 2014.

Krishnan Probability Score

Score 0.49104087079795

Ranking 5829/25841 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 0.99999977242452

Ranking 225/18225 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 0.31791640295872

Ranking 194/18665 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 0.15500090746705

Ranking 5076/20870 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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