CD247
protein-codingCD247 molecule, the group of CD molecules
Gene summary
The protein encoded by this gene is T-cell receptor zeta, which together with T-cell receptor alpha/beta and gamma/delta heterodimers, and with CD3-gamma, -delta and -epsilon, forms the T-cell receptor-CD3 complex. The zeta chain plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways. Low expression of the antigen results in impaired immune response. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
- CD3Z
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~93.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0012426
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0015703
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012426
Submitter: ClinGen
CD247 was first reported in relation to autosomal recessive immunodeficiency 25 in 2006 (Rieux-Laucat et al., PMID: 16672702). Immunodeficiency 25 is a T-B+NK+ severe combined immunodeficiency (SCID). Three variants (nonsense, initiator codon, and extension) that have been reported in 3 probands in 3 publications (PMIDs: 16672702, 27555457, 17170122) are included in this curation. Affected individuals typically present in infancy with severe, recurrent infections; low T cell counts; and impaired T cell proliferation. The production of autoantibodies has been described (PMID: 16672702); however, evidence for symptomatic autoimmunity is currently lacking. Multiple probands have been identified with somatic reversion in which spontaneously arising somatic mutations recover protein expression (PMID: 16672702, 27555457). Heterozygous carriers are reported as unaffected (PMID: 27555457). The mechanism of pathogenicity appears to be loss of function. This gene-disease association is supported by expression studies, protein interactions, functional assays, and animal models (PMIDs: 18853439, 31461748, 1717999, 27555457, 8223444, 8223445). CD247 is expressed in lymphoid tissues and encodes the zeta chain of the T-cell receptor (TCR) complex (PMID: 18853439). The TCR is made up of multiple other CD3 chains including gamma (CD3G gene) and epsilon (CD3E gene) (PMID: 31461748). Extracellular stimulation of the TCR phosphorylates the intracellular zeta chain, and the phosphorylated zeta chain binds a zeta chain associated protein kinase 70 (ZAP70 gene) to initiate downstream signaling (PMID: 1717999). We have previously established that these three genes; CD3E, CD3G, and ZAP70; are definitively associated with severe combined immunodeficiency. Impaired TCR-induced signaling including impaired ZAP70 phosphorylation has also been observed in human T cells that have a CD247 homozygous loss of function variant (PMID: 27555457). CD247 knockout mice have T cell lymphocytopenia and reduced T cell proliferation consistent with SCID (PMID: 8223444, 8223445). In summary, CD247 is definitively associated with autosomal recessive immunodeficiency 25. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen SCID/CID GCEP on February 17, 2022 (SOP Version 8).
Inheritance Pattern: AR
Disease ID:MONDO:0012426
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Gastrointestinal
Intervention: Allergy/Immunology/Infectious
Rationale: Individuals may present with a variety of infectious manifestations, including oral, pulmonary, and skin infections, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; The use of G-CSF has been reported, as has BMT
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CD247 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_198053.3. 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 | 2 | 34 | 2 | 38 | ||
| missense | 3 | 56 | 3 | 62 | ||
| nonsense | 2 | 1 | 1 | 4 | ||
| start loss | 1 | 1 | ||||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 6 | 3 | 60 | 37 | 2 | 108 |
Highest pathogenic variant AF is 0.0002724667
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_932170.1 | 8 | MANE Select | |
| Ensembl | ENSP00000354782.5 | 8 | MANE Select | |
| RefSeq | NP_000725.1 | 8 | Standard | |
| RefSeq | NP_001365444.1 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- T cell receptor signaling pathway - Homo sapiens (human)
- Chagas disease (American trypanosomiasis) - Homo sapiens (human)
- Th17 cell differentiation - Homo sapiens (human)
- Th1 and Th2 cell differentiation - Homo sapiens (human)
- Natural killer cell mediated cytotoxicity - Homo sapiens (human)
Biological Process
- adaptive immune response
- interleukin-2 production
- Fc-gamma receptor signaling pathway involved in phagocytosis
- regulation of defense response to virus by virus
- regulation of immune response
Molecular Function
- transmembrane signaling receptor activity
- protein binding
- identical protein binding
- protein homodimerization activity
- protein tyrosine kinase binding
Cellular Component
- cytoplasm
- plasma membrane
- integral component of membrane
- T cell receptor complex
- alpha-beta T cell receptor complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000362089
- Coding exons
- 8
- Length
- 87971
- Individuals with no LoFs
- 125673
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 74
- Defined
- 125748
- p
- 0.000298
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.307 | 104 | 95.5 | 1.09 | 0.00000620 | 1070 |
| Missense (PolyPhen) | 38 | 37.652 | 1.0092 | 459 | ||
| Synonymous | 0.651 | 33 | 38.1 | 0.866 | 0.00000257 | 302 |
| Loss of Function | 2.01 | 5 | 12.8 | 0.392 | 6.68e-7 | 140 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00029 | 0.00026 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.00074 | 0.00074 | rare |
| European (Non-Finnish) | 0.00036 | 0.00036 | rare |
| South Asian | 0.00020 | 0.00020 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response. When antigen presenting cells (APCs) activate T-cell receptor (TCR), TCR-mediated signals are transmitted across the cell membrane by the CD3 chains CD3D, CD3E, CD3G and CD3Z. All CD3 chains contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic domain. Upon TCR engagement, these motifs become phosphorylated by Src family protein tyrosine kinases LCK and FYN, resulting in the activation of downstream signaling pathways (PubMed:2470098, PubMed:7509083). CD3Z ITAMs phosphorylation creates multiple docking sites for the protein kinase ZAP70 leading to ZAP70 phosphorylation and its conversion into a catalytically active enzyme (PubMed:7509083). Plays an important role in intrathymic T-cell differentiation. Additionally, participates in the activity-dependent synapse formation of retinal ganglion cells (RGCs) in both the retina and dorsal lateral geniculate nucleus (dLGN) (By similarity). {ECO:0000250|UniProtKB:P24161, ECO:0000269|PubMed:16027224, ECO:0000269|PubMed:2470098, ECO:0000269|PubMed:28465009, ECO:0000269|PubMed:7509083}.;
- Disease
- DISEASE: Immunodeficiency 25 (IMD25) [MIM:610163]: An immunological deficiency characterized by T-cells impaired immune response to alloantigens, tetanus toxoid and mitogens. {ECO:0000269|PubMed:16672702}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.130
- RVIS EVS
- -0.34
- RVIS percentile EVS
- 30.07
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.633
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |