Human Gene Module / Chromosome 7 / NFE2L3

NFE2L3nuclear factor, erythroid 2 like 3

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 6
Rare Variants / Common Variants
5 / 0
Aliases
NFE2L3, NRF3
Associated Syndromes
-
Chromosome Band
7p15.2
Associated Disorders
-
Relevance to Autism

De novo likely gene-disruptive (LGD) variants in the NFE2L3 gene have been identified in two ASD probands (Iossifov et al., 2014; Yuen et al., 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified NFE2L3 as a gene with an excess of LGD variants (false discovery rata < 5%, count >1); NFE2L3 was similarly identified as a gene with an excess of de novo LGD variants (false discovery rata < 5%, count >1) following analysis of 5,624 cases with a primary diagnosis of ASD (Coe et al., 2018).

Molecular Function

This gene encodes a member of the cap 'n' collar basic-region leucine zipper family of transcription factors. The encoded protein heterodimerizes with small musculoaponeurotic fibrosarcoma factors to bind antioxidant response elements in target genes. This protein is a membrane bound glycoprotein that is targeted to the endoplasmic reticulum and the nuclear envelope.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to NFE2L3 (6 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 Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
3 Support - Joon-Yong An et al. (2018) Yes -
4 Recent Recommendation Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity Coe BP , et al. (2018) No -
5 Support - Zhou X et al. (2022) Yes -
6 Recent Recommendation - Takumi Nakamura et al. (2024) Yes -
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
C>T - intergenic_variant De novo - Simplex 30545852 Joon-Yong An et al. (2018)
c.1672C>G p.Pro558Ala missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1885A>G p.Lys629Glu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1265_1268del p.Ser422Ter frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.947_948dup p.Glu317MetfsTer30 frameshift_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

De novo likely gene-disruptive (LGD) variants in the NFE2L3 gene have been identified in two ASD probands (Iossifov et al., 2014; Yuen et al., 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified NFE2L3 as a gene with an excess of LGD variants (false discovery rata < 5%, count >1); NFE2L3 was similarly identified as a gene with an excess of de novo LGD variants (false discovery rata < 5%, count >1) following analysis of 5,624 cases with a primary diagnosis of ASD (Coe et al., 2018).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

De novo likely gene-disruptive (LGD) variants in the NFE2L3 gene have been identified in two ASD probands (Iossifov et al., 2014; Yuen et al., 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified NFE2L3 as a gene with an excess of LGD variants (false discovery rata < 5%, count >1); NFE2L3 was similarly identified as a gene with an excess of de novo LGD variants (false discovery rata < 5%, count >1) following analysis of 5,624 cases with a primary diagnosis of ASD (Coe et al., 2018).

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

Increased from to 3

Description

De novo likely gene-disruptive (LGD) variants in the NFE2L3 gene have been identified in two ASD probands (Iossifov et al., 2014; Yuen et al., 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified NFE2L3 as a gene with an excess of LGD variants (false discovery rata < 5%, count >1); NFE2L3 was similarly identified as a gene with an excess of de novo LGD variants (false discovery rata < 5%, count >1) following analysis of 5,624 cases with a primary diagnosis of ASD (Coe et al., 2018).

Krishnan Probability Score

Score 0.33460021607469

Ranking 24451/25841 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 1.0996205279434E-7

Ranking 15670/18225 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 0.76676195846033

Ranking 1735/18665 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 -0.091600427708529

Ranking 12036/20870 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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