Human Gene Module / Chromosome 2 / BIRC6

BIRC6Baculoviral IAP repeat containing 6

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
11 / 13
Rare Variants / Common Variants
49 / 0
Aliases
BIRC6, APOLLON,  BRUCE
Associated Syndromes
-
Chromosome Band
2p22.3
Associated Disorders
-
Relevance to Autism

Three de novo variants in this gene (one nonsense, two missense) have been identified in simplex ASD probands (Iossifov et al., 2012; De Rubeis et al., 2014). Furthermore, an inherited LoF variant in this gene was observed in both affected siblings from a quartet ASD family (Yuen et al., 2015). This gene was also included in a set of genes strongly enriched for those likely to affect risk (FDR < 0.30) (De Rubeis, et al., 2014).

Molecular Function

This gene encodes a protein with a BIR (baculoviral inhibition of apoptosis protein repeat) domain and a UBCc (ubiquitin-conjugating enzyme E2, catalytic) domain that inhibits apoptosis by facilitating the degradation of apoptotic proteins by ubiquitination.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to BIRC6 (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo gene disruptions in children on the autistic spectrum Iossifov I , et al. (2012) Yes -
2 Recent Recommendation Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
3 Recent Recommendation Whole-genome sequencing of quartet families with autism spectrum disorder Yuen RK , et al. (2015) Yes -
4 Recent Recommendation De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia Takata A , et al. (2016) No -
5 Support Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment Chen XS , et al. (2017) No -
6 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
7 Support Genomic Patterns of De Novo Mutation in Simplex Autism Turner TN et al. (2017) Yes -
8 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes Guo H , et al. (2018) Yes -
9 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
10 Support Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort Wu H , et al. (2019) Yes Macrocephaly
11 Support - Alonso-Gonzalez A et al. (2021) Yes -
12 Support - Zhou X et al. (2022) Yes -
13 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (49)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.8341-7T>C - splice_region_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.10563C>G p.Leu3521%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.5207C>T p.Pro1736Leu missense_variant Familial - - 28440294 Chen XS , et al. (2017)
c.10865C>T p.Ala3622Val missense_variant Familial - - 28440294 Chen XS , et al. (2017)
c.491A>C p.Glu164Ala missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.12542C>T p.Ala4181Val missense_variant De novo - Simplex 31674007 Wu H , et al. (2019)
c.3634A>G p.Met1212Val missense_variant De novo - Simplex 30504930 Guo H , et al. (2018)
c.5194G>C p.Val1732Leu missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.10931T>G p.Phe3644Cys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.9578G>C p.Arg3193Pro missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.3223C>T p.Arg1075Ter stop_gained De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.8668C>T p.Arg2890Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.9578G>C p.Arg3193Pro missense_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.3293C>G p.Ala1098Gly missense_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.7662C>T p.Asn2554= synonymous_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.2503C>G p.Arg835Gly missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.3134G>A p.Cys1045Tyr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3587G>T p.Gly1196Val missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4381G>C p.Glu1461Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.5474A>G p.Glu1825Gly missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.9980+3A>T - splice_region_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.511C>T p.Gln171Ter stop_gained Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.11267G>A p.Arg3756His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.11816G>T p.Arg3939Met missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.12857A>G p.Gln4286Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.12967C>T p.Leu4323Phe missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.13084G>A p.Glu4362Lys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.13867A>C p.Asn4623His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.14126C>T p.Pro4709Leu missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3496C>T p.Gln1166Ter stop_gained Familial Paternal Multiplex 25621899 Yuen RK , et al. (2015)
c.3973del p.Ser1325GlnfsTer35 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.5893G>T p.Glu1965Ter stop_gained Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.3590-1G>C - splice_site_variant Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.4070G>A p.Cys1357Tyr missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4873G>C p.Ala1625Pro missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5029C>T p.Pro1677Ser missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.6317C>T p.Ser2106Leu missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.6958C>G p.Pro2320Ala missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.7529C>T p.Ala2510Val missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.9467A>G p.Asn3156Ser missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.10287C>A p.Asp3429Glu missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.11071A>T p.Thr3691Ser missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.11267G>A p.Arg3756His missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.11267G>A p.Arg3756His missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.11998C>T p.Arg4000Cys missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.14152C>T p.Pro4718Ser missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.14294A>G p.Glu4765Gly missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.14294A>G p.Glu4765Gly missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.14399A>T p.His4800Leu missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Three de novo variants in this gene (one nonsense variant, two predicted damaging missense variants) were identified in simplex ASD probands in Iossifov et al., 2012 and De Rubeis et al., 2014. Furthermore, an inherited LoF variant in this gene was observed in both affected siblings from a quartet ASD family in Yuen et al., 2015. This gene was also included in a set of genes strongly enriched for those likely to affect ASD risk (FDR < 0.30) (De Rubeis, et al., 2014).

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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Three de novo variants in this gene (one nonsense variant, two predicted damaging missense variants) were identified in simplex ASD probands in Iossifov et al., 2012 and De Rubeis et al., 2014. Furthermore, an inherited LoF variant in this gene was observed in both affected siblings from a quartet ASD family in Yuen et al., 2015. This gene was also included in a set of genes strongly enriched for those likely to affect ASD risk (FDR < 0.30) (De Rubeis, et al., 2014).

1/1/2021
3
icon
3

Decreased from 3 to 3

Description

Three de novo variants in this gene (one nonsense variant, two predicted damaging missense variants) were identified in simplex ASD probands in Iossifov et al., 2012 and De Rubeis et al., 2014. Furthermore, an inherited LoF variant in this gene was observed in both affected siblings from a quartet ASD family in Yuen et al., 2015. This gene was also included in a set of genes strongly enriched for those likely to affect ASD risk (FDR < 0.30) (De Rubeis, et al., 2014).

Reports Added
[Exploring the biological role of postzygotic and germinal de novo mutations in ASD2021]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Three de novo variants in this gene (one nonsense variant, two predicted damaging missense variants) were identified in simplex ASD probands in Iossifov et al., 2012 and De Rubeis et al., 2014. Furthermore, an inherited LoF variant in this gene was observed in both affected siblings from a quartet ASD family in Yuen et al., 2015. This gene was also included in a set of genes strongly enriched for those likely to affect ASD risk (FDR < 0.30) (De Rubeis, et al., 2014).

Reports Added
[Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort.2019] [New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

Three de novo variants in this gene (one nonsense variant, two predicted damaging missense variants) were identified in simplex ASD probands in Iossifov et al., 2012 and De Rubeis et al., 2014. Furthermore, an inherited LoF variant in this gene was observed in both affected siblings from a quartet ASD family in Yuen et al., 2015. This gene was also included in a set of genes strongly enriched for those likely to affect ASD risk (FDR < 0.30) (De Rubeis, et al., 2014).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
10/1/2018
4
icon
4

Decreased from 4 to 4

Description

Three de novo variants in this gene (one nonsense variant, two predicted damaging missense variants) were identified in simplex ASD probands in Iossifov et al., 2012 and De Rubeis et al., 2014. Furthermore, an inherited LoF variant in this gene was observed in both affected siblings from a quartet ASD family in Yuen et al., 2015. This gene was also included in a set of genes strongly enriched for those likely to affect ASD risk (FDR < 0.30) (De Rubeis, et al., 2014).

Reports Added
[Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.2018]
10/1/2017
icon
4

Increased from to 4

Description

Three de novo variants in this gene (one nonsense variant, two predicted damaging missense variants) were identified in simplex ASD probands in Iossifov et al., 2012 and De Rubeis et al., 2014. Furthermore, an inherited LoF variant in this gene was observed in both affected siblings from a quartet ASD family in Yuen et al., 2015. This gene was also included in a set of genes strongly enriched for those likely to affect ASD risk (FDR < 0.30) (De Rubeis, et al., 2014).

Reports Added
[Genomic Patterns of De Novo Mutation in Simplex Autism2017]
Krishnan Probability Score

Score 0.49132266810206

Ranking 5645/25841 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

Ranking 17/18225 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 0.4668384220269

Ranking 382/18665 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 0.14884592582425

Ranking 5210/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
AGRP Agouti-related protein Human Protein Binding 181 O00253
AKAP9 A kinase (PRKA) anchor protein (yotiao) 9 Human Protein Binding 10142 Q99996
ANGPTL3 angiopoietin-like 3 Human Protein Binding 27329 Q9Y5C1
C3ORF20 Uncharacterized protein C3orf20 Human Protein Binding 84077 Q8ND61-2
CCDC22 coiled-coil domain containing 22 Human Protein Binding 28952 O60826
CHIA Acidic mammalian chitinase Human Protein Binding 27159 Q9BZP6-2
DCAF12 DDB1 and CUL4 associated factor 12 Human Protein Binding 25853 Q5T6F0
DIABLO diablo, IAP-binding mitochondrial protein Human Protein Binding 56616 Q9NR28
FAM58A Cyclin-related protein FAM58A Human Protein Binding 92002 Q8N1B3-2
FERMT2 fermitin family member 2 Human Protein Binding 10979 Q96AC1
FIGF c-fos induced growth factor (vascular endothelial growth factor D) Human Protein Binding 2277 O43915
INTS4L2 Human Protein Binding Q2T9F4
MGST3 Microsomal glutathione S-transferase 3 Human Protein Binding 4259 O14880
MOS v-mos Moloney murine sarcoma viral oncogene homolog Human Protein Binding 4342 P00540
NINL ninein-like Human Protein Binding 22981 Q9Y2I6
OSBPL2 oxysterol binding protein-like 2 Human Protein Binding 9885 Q9H1P3
PSMC5 proteasome (prosome, macropain) 26S subunit, ATPase, 5 Human Protein Binding 5705 P62195
UGGT2 UDP-glucose glycoprotein glucosyltransferase 2 Human Protein Binding 55757 Q05D90
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