TM4SF20
protein-codingtransmembrane 4 L six family member 20
Gene summary
The protein encoded by this gene is a member of the four-transmembrane L6 superfamily. Members of this family function in various cellular processes including cell proliferation, motility, and adhesion via their interactions with integrins. In human brain tissue, this gene is expressed at high levels in the parietal lobe, occipital lobe, hippocampus, pons, white matter, corpus callosum, and cerebellum. Knockout of the homologous gene in mouse results in a neurobehavioral phenotype with suggested enhanced motor coordination. A deletion mutation in the human gene is associated with specific language impairment-5. [provided by RefSeq, Jul 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~20.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014184
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014184
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TM4SF20 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_024795.4. 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 | 14 | 3 | 17 | |||
| missense | 63 | 8 | 3 | 74 | ||
| nonsense | 2 | 2 | ||||
| start loss | 0 | |||||
| frameshift | 3 | 3 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 3 | 4 | |||
| Total | 1 | 0 | 71 | 22 | 6 | 100 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_079071.2 | 4 | MANE Select | |
| Ensembl | ENSP00000303028.3 | 4 | MANE Select | |
| Ensembl | ENSP00000416565.1 | 1 | Standard | |
| Ensembl | ENSP00000766255.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- negative regulation of proteolysis
Cellular Component
- endoplasmic reticulum membrane
- plasma membrane
- focal adhesion
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000304568
- Coding exons
- 4
- Length
- 19840
- Individuals with no LoFs
- 125719
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 28
- Defined
- 125747
- p
- 0.000111
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.396 | 131 | 119 | 1.10 | 0.00000550 | 1501 |
| Missense (PolyPhen) | 49 | 46.227 | 1.06 | 572 | ||
| Synonymous | 0.306 | 43 | 45.6 | 0.942 | 0.00000244 | 449 |
| Loss of Function | 0.340 | 6 | 6.97 | 0.861 | 2.94e-7 | 90 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.00031 | 0.00030 | rare |
| East Asian | 0.000055 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00018 | 0.00018 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Polytopic transmembrane protein that inhibits regulated intramembrane proteolysis (RIP) of CREB3L1, inhibiting its activation and the induction of collagen synthesis (PubMed:25310401, PubMed:27499293). In response to ceramide, which alters TM4SF20 membrane topology, stimulates RIP activation of CREB3L1 (PubMed:27499293). Ceramide reverses the direction through which transmembrane helices are translocated into the endoplasmic reticulum membrane during translation of TM4SF20, this mechanism is called 'regulated alternative translocation' (RAT) and regulates the function of the transmembrane protein (PubMed:27499293). {ECO:0000269|PubMed:25310401, ECO:0000269|PubMed:27499293}.;
- Disease
- DISEASE: Specific language impairment 5 (SLI5) [MIM:615432]: A disorder characterized by a delay in early speech acquisition. It is usually associated with cerebral white matter abnormalities on brain MRI. Some individuals may show disorders in communication, consistent with autism spectrum disorder, or global developmental delay, although others ultimately show normal cognitive function. Penetrance is incomplete and expressivity is variable. {ECO:0000269|PubMed:23810381}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.0835
Intolerance Scores
- LoFtool
- 0.824
- RVIS EVS
- 0.71
- RVIS percentile EVS
- 85.53
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.231
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |