Human Gene Module / Chromosome 19 / ETFB

ETFBElectron-transfer-flavoprotein, beta polypeptide

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 5
Rare Variants / Common Variants
12 / 0
Aliases
ETFB, FP585,  MADD
Associated Syndromes
-
Chromosome Band
19q13.41
Associated Disorders
-
Relevance to Autism

This gene was identified in an ASD whole-exome sequencing study and subsequent TADA (transmission and de novo association) analysis as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (De Rubeis et al., 2014).

Molecular Function

This gene encodes electron-transfer-flavoprotein, beta polypeptide, which shuttles electrons between primary flavoprotein dehydrogenases involved in mitochondrial fatty acid and amino acid catabolism and the membrane-bound electron transfer flavoprotein ubiquinone oxidoreductase. Deficiencies in this gene have been implicated in glutaric aciduria 2B (GA2B) [MIM:231680].

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ETFB (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations O'Roak BJ , et al. (2012) Yes -
2 Recent Recommendation Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
3 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
4 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
5 Support - Zhou X et al. (2022) Yes -
Rare Variants   (12)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.712-4C>T - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.380A>G p.His127Arg missense_variant De novo - - 28714951 Lim ET , et al. (2017)
c.217G>A p.Ala73Thr missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.991G>T p.Glu331Ter stop_gained De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
c.1021A>T p.Lys341Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
TCA>T - frameshift_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.697C>T p.Leu233Phe missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.748A>T p.Lys250Ter stop_gained Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.263dup p.Leu88PhefsTer14 frameshift_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.697C>T p.Leu233Phe missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.355G>A p.Gly119Ser missense_variant Familial Paternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.500G>A p.Arg167His missense_variant Familial Maternal Multiplex 25363760 De Rubeis S , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo LoF variant in the ETFB gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22495309). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ETFB as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760).

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

A de novo LoF variant in the ETFB gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22495309). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ETFB as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760).

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2017
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant in the ETFB gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22495309). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ETFB as a gene meeting high statistical significance with a 0.05 < FDR ? 0.1, meaning that this gene had a ? 90% chance of being a true autism gene (PMID 25363760).

Reports Added
[Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.2017]
10/1/2014
icon
3

Increased from to 3

Description

A de novo LoF variant in the ETFB gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22495309). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ETFB as a gene meeting high statistical significance with a 0.05

Krishnan Probability Score

Score 0.28365678205199

Ranking 25506/25841 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 0.0037161629162995

Ranking 10807/18225 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 0.057802163278829

Ranking 49/18665 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
Larsen Cumulative Evidence Score

Score 23

Ranking 86/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score -0.76104068204406

Ranking 20557/20870 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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