Human Gene Module / Chromosome 18 / MIB1

MIB1Mindbomb E3 ubiquitin protein ligase 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
10 / 10
Rare Variants / Common Variants
31 / 0
EAGLE Score
3.6
Limited Learn More
Aliases
MIB1, DIP-1,  DIP1,  LVNC7,  MIB,  ZZANK2,  ZZZ6
Associated Syndromes
-
Chromosome Band
18q11.2
Associated Disorders
-
Genetic Category
Rare Single Gene Mutation
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 a protein that functions as an E3 ubiquitin ligase. The encoded protein positively regulates Notch signaling by ubiquitinating the Notch receptors, thereby facilitating their endocytosis. This protein may also promote the ubiquitination and degradation of death-associated protein kinase 1 (DAPK1).

SFARI Genomic Platforms
Reports related to MIB1 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support Whole-genome sequencing of quartet families with autism spectrum disorder Yuen RK , et al. (2015) Yes -
4 Support Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci Sanders SJ , et al. (2015) Yes -
5 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
6 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
7 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
8 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
9 Support - Zhou X et al. (2022) Yes -
10 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (31)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.289C>T p.Arg97Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.2305C>T p.Arg769Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.2321A>G p.Gln774Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1134C>T p.Asp378= synonymous_variant De novo - - 31452935 Feliciano P et al. (2019)
c.75dup p.Trp26ValfsTer56 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.1479+2T>G - splice_site_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1830-2A>C - splice_site_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1328A>G p.Asp443Gly missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.1588C>T p.Arg530Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2716C>T p.Arg906Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2962C>T p.Arg988Cys missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.2327C>G p.Pro776Arg missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.309T>G p.Cys103Trp missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2405G>A p.Gly802Asp missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2743G>A p.Gly915Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2746G>A p.Gly916Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2906G>A p.Arg969His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.532-2A>C - splice_site_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.289C>T p.Arg97Ter stop_gained Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1111C>T p.Arg371Ter stop_gained Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.2716C>T p.Arg906Ter stop_gained Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.836T>G p.Leu279Ter stop_gained Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2394-2A>G - splice_site_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1588C>T p.Arg530Ter stop_gained Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2305C>T p.Arg769Ter stop_gained Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2716C>T p.Arg906Ter stop_gained Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1039C>T p.Arg347Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.2673del p.Asn892ThrfsTer2 frameshift_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2717del p.Arg906GlnfsTer62 frameshift_variant Familial Paternal Multiplex 25621899 Yuen RK , et al. (2015)
c.435dup p.Ile146AspfsTer30 frameshift_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1901del p.Thr634MetfsTer12 frameshift_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

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 MIB1 as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760).

Score Delta: Score remained at 2

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

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 MIB1 as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760).

1/1/2020
3
icon
3

Decreased from 3 to 3

Description

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 MIB1 as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

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 MIB1 as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760).

7/1/2019
4
icon
4

Decreased from 4 to 4

Description

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 MIB1 as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760).

7/1/2017
4
icon
4

Decreased from 4 to 4

Description

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 MIB1 as a gene meeting high statistical significance with a 0.01 < FDR ? 0.05, meaning that this gene had a ? 95% chance of being a true autism gene (PMID 25363760).

1/1/2016
4
icon
4

Decreased from 4 to 4

Description

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 MIB1 as a gene meeting high statistical significance with a 0.01

10/1/2014
icon
4

Increased from to 4

Description

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 MIB1 as a gene meeting high statistical significance with a 0.01

Krishnan Probability Score

Score 0.4952228753076

Ranking 3110/25841 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 1.0007180499768E-44

Ranking 18211/18225 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 0.047428125547235

Ranking 45/18665 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).
Larsen Cumulative Evidence Score

Score 31

Ranking 70/461 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.
Zhang D Score

Score -0.035204736663941

Ranking 9871/20870 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.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
Acsbg1 acyl-CoA synthetase bubblegum family member 1 Rat Protein Binding 171410 Q924N5
Adgrl3 adhesion G protein-coupled receptor L3 Rat Protein Binding 170641 Q9Z173
Ankrd34c ankyrin repeat domain 34C Rat Protein Binding 300889 D3ZI64
ANKRD55 Ankyrin repeat domain-containing protein 55 Human Protein Binding 79722 Q3KP44-2
Arg1 arginase 1 Rat Protein Binding 29221 P07824
Arhgef25 Rho guanine nucleotide exchange factor 25 Rat Protein Binding 314904 Q6P720
Atp2a3 ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 3 Rat Protein Binding 25391 P18596
Bco2 beta-carotene oxygenase 2 Rat Protein Binding 315644 A3KN98
Bgn biglycan Rat Protein Binding 25181 P47853
C1qb complement component 1, q subcomponent, B chain Rat Protein Binding 29687 P31721
C1qc complement component 1, q subcomponent, C chain Rat Protein Binding 362634 P31722
C2cd5 C2 calcium-dependent domain containing 5 Rat Protein Binding 362461 D4A5B3
Cacng8 calcium voltage-gated channel auxiliary subunit gamma 8 Rat Protein Binding 140729 Q8VHW5
Car10 carbonic anhydrase 10 Rat Protein Binding 100360015 M0R8A5
Casq2 calsequestrin 2 Rat Protein Binding 29209 P51868
Cbln3 cerebellin 3 precursor Rat Protein Binding 501998 D3Z9H1
Ccar2 cell cycle and apoptosis regulator 2 Rat Protein Binding 306007 F1LM55
CHRNA3 Neuronal acetylcholine receptor subunit alpha-3 Human Protein Binding 1136 P32297-1
Col1a1 collagen, type I, alpha 1 Rat Protein Binding 29393 P02454
Coro1a coronin 1A Rat Protein Binding 155151 Q91ZN1
Coro6 coronin 6 Rat Protein Binding 245982 Q920J3
Crym crystallin, mu Rat Protein Binding 117024 Q9QYU4
Dhrs4 dehydrogenase/reductase (SDR family) member 4 Rat Protein Binding 266686 Q8VID1
Dll4 delta-like 4 (Drosophila) Mouse Protein Binding 54485 Q9JI71
EPN3 Epsin-3 Human Protein Binding 55040 Q9H201-2
Erbin erbb2 interacting protein Rat Protein Binding 365661
Fam109a family with sequence similarity 109, member A Rat Protein Binding 288664 D3ZL52
Gkap1 G kinase anchoring protein 1 Rat Protein Binding 361202 Q5XIG5
Gpc3 glypican 3 Rat Protein Binding 25236 P13265
Gpc4 glypican 4 Rat Protein Binding 317322 Q642B0
Gsdma gasdermin A Rat Protein Binding 360619 D3ZA32
Gsta5 glutathione S-transferase alpha 5 Rat Protein Binding 494499 P04903
Gstm1 glutathione S-transferase mu 1 Rat Protein Binding 24423 P04905
Gstm5 glutathione S-transferase, mu 5 Rat Protein Binding 64352 Q9Z1B2
Gstm6 glutathione S-transferase, mu 6 Rat Protein Binding 499688 B0BN47
Hist1h2bb histone cluster 1, H2bb Rat Protein Binding 679910
Hmgcs2 3-hydroxy-3-methylglutaryl-CoA synthase 2 Rat Protein Binding 24450 Q68G44
Hnrnpdl heterogeneous nuclear ribonucleoprotein D-like Rat Protein Binding 305178 Q3SWU3
Htra1 HtrA serine peptidase 1 Rat Protein Binding 65164 Q9QZK5
Htra2 HtrA serine peptidase 2 Rat Protein Binding 297376 B0BNB9
Igh-6 immunoglobulin heavy chain 6 Rat Protein Binding 299357 Q569B3
Kb15 type II keratin Kb15 Rat Protein Binding 366992 A0A0G2JVA8
LOC100910660 serine/arginine-rich splicing factor 3-like Rat Protein Binding 100910660 Q0ZFS8
LOC360933 similar to Ac1591 Rat Protein Binding 360933 Q7TQ71
LOC501110 similar to Glutathione S-transferase A1 (GTH1) (HA subunit 1) (GST-epsilon) (GSTA1-1) (GST class-alpha) Rat Protein Binding 501110 Q6AXY0
LRRCC1 Leucine-rich repeat and coiled-coil domain-containing protein 1 Human Protein Binding 85444 Q9C099-2
Nccrp1 non-specific cytotoxic cell receptor protein 1 homolog (zebrafish) Rat Protein Binding 292755 D3ZQ18
Phyhipl phytanoyl-CoA 2-hydroxylase interacting protein-like Rat Protein Binding 309901 Q6AYN4
Plbd1 phospholipase B domain containing 1 Rat Protein Binding 297694 Q5U2V4
Plg plasminogen Rat Protein Binding 85253 Q01177
Plppr4 phospholipid phosphatase related 4 Rat Protein Binding 295401 G3V864
Prss1 protease, serine 1 Rat Protein Binding 24691 P00762
Rbmxrtl RNA binding motif protein, X chromosome retrogene-like Rat Protein Binding 307779 P84586
RGD1304704 similar to Hypothetical protein CGI-99 Rat Protein Binding 302247 F7EMB2
RGD1306195 similar to RAN protein Rat Protein Binding 313163 Q66H11
RGD1562399 similar to 40S ribosomal protein S2 Rat Protein Binding 301438 D3ZAS1
RGD1563613 similar to 40S ribosomal protein S25 Rat Protein Binding 366605 D4AE10
RGD1564606 similar to 60S ribosomal protein L23a Rat Protein Binding 499523 F1LT35
Rpl5l1 ribosomal protein L5-like 1 Rat Protein Binding 501206 D3ZHP8
Rsu1 Ras suppressor protein 1 Rat Protein Binding 680419 D4A8F2
Rundc3b RUN domain containing 3B Rat Protein Binding 688590 Q3B7K9
Sdpr serum deprivation response Rat Protein Binding 316384 Q66H98
Sema5a semaphorin 5A Rat Protein Binding 310207 D3ZTD8
Sept2 septin 2 Rat Protein Binding 117515 Q91Y81
Serpinb13 serpin peptidase inhibitor, clade B (ovalbumin), member 13 Rat Protein Binding 304690 D3ZKA0
Spock1 sparc/osteonectin, cwcv and kazal-like domains proteoglycan (testican) 1 Rat Protein Binding 306759 Q562B0
Spock2 sparc/osteonectin, cwcv and kazal-like domains proteoglycan (testican) 2 Rat Protein Binding 361840 A0A0G2K946
Tfpi tissue factor pathway inhibitor Rat Protein Binding 29436 Q02445
Tgm1 transglutaminase 1 Rat Protein Binding 60335 P23606
Zc2hc1a zinc finger, C2HC-type containing 1A Rat Protein Binding 310244 B5DF95
Zfp598 zinc finger protein 598 Rat Protein Binding 287119 D3ZR64
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