Human Gene Module / Chromosome 14 / IRF2BPL

IRF2BPLInterferon regulatory factor 2 binding protein-like

Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
3 / 5
Rare Variants / Common Variants
20 / 0
Aliases
IRF2BPL, C14orf4,  EAP1
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
14q24.3
Associated Disorders
ASD
Relevance to Autism

This gene was identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant.

Molecular Function

This gene encodes a transcription factor that may play a role in regulating female reproductive function. It may play a role in gene transcription by transactivating the GNRH1 promoter and repressing the PENK promoter.

Reports related to IRF2BPL (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
2 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
3 Primary Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci. Sanders SJ , et al. (2015) Yes -
4 Recent Recommendation IRF2BPL Is Associated with Neurological Phenotypes. Marcogliese PC , et al. (2018) No -
5 Recent Recommendation De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy. Tran Mau-Them F , et al. (2018) No ASD
Rare Variants   (20)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
2103+A (delT) 701-! frameshift_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.90C>G p.Phe30Leu missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.514C>T p.Glu172Ter stop_gained De novo - - 30057031 Marcogliese PC , et al. (2018)
c.562C>T p.Arg188Ter stop_gained Unknown - - 30057031 Marcogliese PC , et al. (2018)
c.562C>T p.Arg188Ter stop_gained De novo - - 30057031 Marcogliese PC , et al. (2018)
c.379C>T p.Gln127Ter stop_gained Unknown - - 30057031 Marcogliese PC , et al. (2018)
c.376C>T p.Gln126Ter stop_gained De novo - - 30057031 Marcogliese PC , et al. (2018)
c.1115C>G p.Pro372Arg missense_variant De novo - - 30057031 Marcogliese PC , et al. (2018)
c.1254G>C p.Lys418Asn missense_variant De novo - - 30057031 Marcogliese PC , et al. (2018)
c.519C>G p.Tyr173Ter stop_gained De novo - - 30166628 Tran Mau-Them F , et al. (2018)
c.361C>T p.Gln121Ter stop_gained De novo - - 30166628 Tran Mau-Them F , et al. (2018)
c.376C>T p.Gln126Ter stop_gained De novo - - 30166628 Tran Mau-Them F , et al. (2018)
c.496G>T p.Glu166Ter stop_gained De novo - - 30166628 Tran Mau-Them F , et al. (2018)
c.519C>G p.Tyr173Ter stop_gained De novo - - 30166628 Tran Mau-Them F , et al. (2018)
c.562C>T p.Arg188Ter stop_gained De novo - - 30166628 Tran Mau-Them F , et al. (2018)
c.962delC p.Ala321GlufsTer24 frameshift_variant De novo - - 30166628 Tran Mau-Them F , et al. (2018)
c.2122delG p.Ala708ProfsTer59 frameshift_variant De novo - - 30166628 Tran Mau-Them F , et al. (2018)
c.2135_2136delGT p.Leu713SerfsTer56 frameshift_variant De novo - - 30166628 Tran Mau-Them F , et al. (2018)
- p.Cys714AlafsTer49 frameshift_variant De novo - - 30166628 Tran Mau-Them F , et al. (2018)
c.2152delT p.Cys718AlafsTer48 frameshift_variant De novo - - 30166628 Tran Mau-Them F , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

2

Score Delta: Score remained at 2.1

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.

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."

10/1/2015
icon
2

Increased from to 2

Description

This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). This gene was subsequently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant.

Krishnan Probability Score

Score 0.49631658011089

Ranking 2624/25841 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 0.9689353461122

Ranking 2385/18225 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 0.958

Ranking 74/239 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 0.086375716290276

Ranking 60/18665 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 0.14060358626709

Ranking 5348/20870 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.
CNVs associated with IRF2BPL(1 CNVs)
14q24.3 19 Deletion-Duplication 31  /  84
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