EFTUD2
protein-codingelongation factor Tu GTP binding domain containing 2, the group of Spliceosomal C complex|U5 small nuclear ribonucleoprotein|Spliceosomal Bact complex|Spliceosomal P complex
Gene summary
This gene encodes a GTPase which is a component of the spliceosome complex which processes precursor mRNAs to produce mature mRNAs. Mutations in this gene are associated with mandibulofacial dysostosis with microcephaly. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~49.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0012516
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0012516
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0012516
Submitter: ClinGen
*EFTUD2* variants were first reported in relation to autosomal dominant mandibulofacial dysostosis-microcephaly syndrome (MFDM) in 2012 (PMID: 22305528). *EFTUD2* encodes a GTPase subunit of the U5 small nuclear ribonucleoprotein complex of the spliceosome. MFDM is characterized by global developmental delay, intellectual disability, microcephaly, craniofacial skeletal anomalies, and abnormalities of the ears and hearing (PMIDs: 22305528, 24999515, 35395430). To date, at least 126 MFDM patients have been reported with *EFTUD2* variants, including large deletions, nonsense, frameshift, splice site, and missense variants (PMIDs: 22305528, 24999515, 35395430). Nine unique variants reported in nine probands (PMIDs: 22305528, 35395430) are included in this curation. Most cases are *de novo*, although inheritance from mildly affected parents has been reported in rare cases (PMID: 24999515). The mechanism of pathogenicity is haploinsufficiency. Homozygous *EFTUD2* knock-out zebrafish and mice with a homozygous conditional *EFTUD2* knock-out in neural crest cells display abnormal brain development, abnormal craniofacial malformations, and abnormal splicing, which further supports the gene-disease relationship (PMIDs: 27899647, 33601405). In summary, there is definitive evidence supporting the relationship between *EFTUD2* and autosomal dominant mandibulofacial dysostosis-microcephaly syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 20, 2022 (SOP Version 8).
Inheritance Pattern: AD
Disease ID:MONDO:0012516
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0012516
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Gastrointestinal; Musculoskeletal; Neurologic
Intervention: Audiologic/Otolaryngologic; Cardiovascular
Rationale: Though the condition may be recognizable, early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Recognition of potential GI manifestations (eg, Hirschsprung disease) may allow prompt treatment; The condition can involve congenital cardiac anomalies, and awareness may allow early management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to EFTUD2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004247.4. 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 | 1 | 2 | 17 | 148 | 1 | 169 |
| missense | 6 | 24 | 298 | 36 | 3 | 367 |
| nonsense | 20 | 12 | 32 | |||
| start loss | 1 | 1 | ||||
| frameshift | 52 | 26 | 78 | |||
| splice donor/acceptor (+/-2bp) | 23 | 29 | 12 | 64 | ||
| Total | 103 | 93 | 327 | 184 | 4 | 711 |
Highest pathogenic variant AF is 0.0000065700433
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004238.3 | 27 | MANE Select | |
| Ensembl | ENSP00000392094.1 | 27 | MANE Select | |
| RefSeq | NP_001136077.1 | 26 | Standard | |
| RefSeq | NP_001245282.1 | 27 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| eftud2 | Danio rerio | Structure: neuroblast (sensu Vertebrata) Quality: increased occurrence abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Spliceosome - Homo sapiens (human)
- mRNA Processing
- Metabolism of RNA
- mRNA Splicing - Major Pathway
- mRNA Splicing - Minor Pathway
Biological Process
- mRNA splicing, via spliceosome
- mRNA processing
- RNA splicing
- cellular response to drug
- response to cocaine
Molecular Function
- RNA binding
- GTPase activity
- protein binding
- GTP binding
- U5 snRNA binding
Cellular Component
- nucleoplasm
- spliceosomal complex
- cytosol
- Cajal body
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000426333
- Coding exons
- 27
- Length
- 49720
- Individuals with no LoFs
- 125713
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 125714
- p
- 0.00000398
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.03 | 293 | 561 | 0.522 | 0.0000314 | 6417 |
| Missense (PolyPhen) | 75 | 243.93 | 0.30746 | 2766 | ||
| Synonymous | 0.545 | 212 | 222 | 0.954 | 0.0000135 | 1870 |
| Loss of Function | 6.45 | 1 | 50.4 | 0.0198 | 0.00000247 | 610 |
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 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the U5 snRNP and the U4/U6-U5 tri-snRNP complex required for pre-mRNA splicing. Binds GTP.;
- Disease
- DISEASE: Mandibulofacial dysostosis with microcephaly (MFDM) [MIM:610536]: A rare syndrome characterized by progressive microcephaly, midface and malar hypoplasia, micrognathia, microtia, dysplastic ears, preauricular skin tags, significant developmental delay, and speech delay. Many patients have major sequelae, including choanal atresia that results in respiratory difficulties, conductive hearing loss, and cleft palate. {ECO:0000269|PubMed:22305528}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.337
Intolerance Scores
- LoFtool
- 0.0218
- RVIS EVS
- -1.15
- RVIS percentile EVS
- 6.23
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.989
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |