MID1
protein-codingmidline 1, the group of Tripartite motif family|Ring finger proteins|Fibronectin type III domain containing
Gene summary
The protein encoded by this gene is a member of the tripartite motif (TRIM) family, also known as the 'RING-B box-coiled coil' (RBCC) subgroup of RING finger proteins. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. This protein forms homodimers which associate with microtubules in the cytoplasm. The protein is likely involved in the formation of multiprotein structures acting as anchor points to microtubules. Mutations in this gene have been associated with the X-linked form of Opitz syndrome, which is characterized by midline abnormalities such as cleft lip, laryngeal cleft, heart defects, hypospadias, and agenesis of the corpus callosum. This gene was also the first example of a gene subject to X inactivation in human while escaping it in mouse. Alternative promoter use, alternative splicing and alternative polyadenylation result in multiple transcript variants that have different tissue specificities. [provided by RefSeq, Dec 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~388.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0010222
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010222
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0010222
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010222
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0010222
Submitter: ClinGen
*MID1* is located on chromosome Xp22.2 and encodes a microtubule-associated E3 ubiquitin ligase that regulates the degradation of the catalytic subunit of protein phosphatase 2A (PP2Ac). *MID1* was first reported in relation to X-linked Opitz G/BBB syndrome in 1997 (Quaderi et al., PMID: 9354791). Opitz G/BBB syndrome is a congenital midline malformation syndrome characterized by hypertelorism, hypospadias, laryngotracheoesophageal defects, cleft lip/palate, congenital heart defects, and midline defects of the brain, including agenesis of the corpus callosum and cerebellar vermis agenesis or hypoplasia. The phenotype is highly variable, even within the same family. Intellectual disability/developmental delay (ID/DD) are observed in about 15%-50% of affected males. A review of the clinical phenotypes of 85 affected males with *MID1* variants showed that about one-third have ID/DD (PMID: 26788540). Female carriers usually present with isolated hypertelorism and only rarely exhibit other manifestations. Sixteen variants (6 nonsense, 6 frameshift, 3 missense, and 1 in-frame deletion) that have been reported in 16 probands in 4 publications (PMIDs: 11030761, 12833403, 15121778, 17221865) are included in this curation. Variants in this gene segregated with disease in additional family members. The variants occurred *de novo* in 5 probands and were maternally inherited in the remaining cases. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Among the 16 cases curated here, 6 have ID/DD, 7 do not have ID/DD, and 3 have no information. The mechanism of pathogenicity is loss of function. Variants near the C-terminus of *MID1* abolish or significantly reduce microtubule association (PMIDs: 10077590, 11030761), while other variants can still bind to microtubules but cannot be actively transported (PMID: 18949047). MID1 loss of function disrupts the formation of the MID1-α4-PP2Ac complex, leading to increased PP2A levels and downregulation of mTORC1 signaling (PMID: 21555591). This gene-disease relationship is also supported by *Mid1* knockout mouse models (PMIDs: 20181585, 24194544). In summary, there is definitive evidence supporting the relationship between *MID1* and X-linked Opitz G/BBB syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on March 21, 2018. It was reevaluated on August 5, 2026 (SOP Version 12). As a result of this reevaluation, the classification did not change.
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Gastrointestinal; Genitourinary; Neurologic
Intervention: Cardiovascular
Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MID1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000381.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 12 | 143 | 24 | 179 | ||
| missense | 5 | 9 | 183 | 29 | 7 | 233 |
| nonsense | 14 | 9 | 7 | 30 | ||
| start loss | 0 | |||||
| frameshift | 18 | 14 | 32 | |||
| splice donor/acceptor (+/-2bp) | 6 | 6 | 11 | 23 | ||
| Total | 43 | 38 | 213 | 172 | 31 | 497 |
Highest pathogenic variant AF is 0.000008918459
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000372.1 | 9 | MANE Select | |
| Ensembl | ENSP00000312678.4 | 9 | MANE Select | |
| RefSeq | NP_001092094.1 | 9 | Standard | |
| RefSeq | NP_001180206.1 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Ubiquitin mediated proteolysis - Homo sapiens (human)
- Cytokine Signaling in Immune system
- Immune System
- Interferon gamma signaling
- Interferon Signaling
Biological Process
- microtubule cytoskeleton organization
- negative regulation of microtubule depolymerization
- pattern specification process
- positive regulation of stress-activated MAPK cascade
- protein localization to microtubule
Molecular Function
- protein binding
- microtubule binding
- zinc ion binding
- transferase activity
- ubiquitin protein ligase binding
Cellular Component
- spindle
- cytosol
- microtubule
- microtubule associated complex
- cytoplasmic microtubule
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000317552
- Coding exons
- 9
- Length
- 438424
- Individuals with no LoFs
- 125716
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 125719
- p
- 0.0000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.92 | 152 | 293 | 0.519 | 0.0000252 | 4402 |
| Missense (PolyPhen) | 37 | 116.77 | 0.31686 | 1732 | ||
| Synonymous | -0.187 | 122 | 119 | 1.02 | 0.0000107 | 1298 |
| Loss of Function | 3.81 | 2 | 20.7 | 0.0965 | 0.00000160 | 336 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00022 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000012 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Has E3 ubiquitin ligase activity towards IGBP1, promoting its monoubiquitination, which results in deprotection of the catalytic subunit of protein phosphatase PP2A, and its subsequent degradation by polyubiquitination. {ECO:0000269|PubMed:10400985, ECO:0000269|PubMed:11685209, ECO:0000269|PubMed:22613722}.;
- Disease
- DISEASE: Opitz GBBB syndrome 1 (GBBB1) [MIM:300000]: A congenital midline malformation syndrome characterized by hypertelorism, genital-urinary defects such as hypospadias in males and splayed labia in females, cleft lip/palate, laryngotracheoesophageal abnormalities, imperforate anus, developmental delay and congenital heart defects. {ECO:0000269|PubMed:11030761, ECO:0000269|PubMed:15558842, ECO:0000269|PubMed:9354791, ECO:0000269|PubMed:9718340}. Note=The disease is caused by mutations affecting the gene represented in this entry. MID1 mutations produce proteins with a decreased affinity for microtubules.;
Recessive Scores
- pRec
- 0.290
Intolerance Scores
- LoFtool
- 0.448
- RVIS EVS
- -0.78
- RVIS percentile EVS
- 12.77
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.801
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |