CD3E

protein-coding

CD3 epsilon subunit of T-cell receptor complex, the group of CD molecules

Gene summary

The protein encoded by this gene is the CD3-epsilon polypeptide, which together with CD3-gamma, -delta and -zeta, and the T-cell receptor alpha/beta and gamma/delta heterodimers, forms the T-cell receptor-CD3 complex. This complex plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways. The genes encoding the epsilon, gamma and delta polypeptides are located in the same cluster on chromosome 11. The epsilon polypeptide plays an essential role in T-cell development. Defects in this gene cause immunodeficiency. This gene has also been linked to a susceptibility to type I diabetes in women. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000733.4

Inheritance

ClinVar variants

P:21U:69B:68

Top phenotype

Immunodeficiency 18

gnomAD constraint

pLI —, LoF o/e 0.51

Max pathogenic AF

—

Genomic locus

chr11:118,304,730-118,316,175

External References & Databases

Ensembl (ENSG00000198851)

Transcript & Mutation Effects

hg38 • Region Span ~11.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zetaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015703

Submitter: Orphanet

immunodeficiency 18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014278

Submitter: Labcorp Genetics (formerly Invitae)

immunodeficiency 18DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014278

Submitter: ClinGen

CD3E was first reported in relation to autosomal recessive immunodeficiency 18 in 1993 (Soudais et al., PMID: 8490660). CD3ε deficiency results in an absence of mature TCR αβ and γδ T cells in the periphery whereas natural killer and B lymphocytes were normally detected, causing T−, B+, NK+ SCID. At least 8 variants predicted to cause a loss of function of the protein have been reported, suggesting biallelic loss of function is the molecular mechanism. Evidence supporting the gene-disease relationship includes the identification of at least 8 probands with CD3E variants who have been reported in at least 8 publications (PMID: 8490660, 28916186, 15546002, 27807805, 28597365, 24515816, 31589898, 32016651). This gene-disease relationship is also supported by animal models (PMIDs: 9843989, 9885898, 7588594), rescue experiments (PMID: 9843989), and expression studies (PMIDs: 3012357, 2410254). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. In summary, CD3E is definitively associated with autosomal recessive immunodeficiency 18. 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 Working Group on 01/21/2021.

Clinical Genomic Database (CGD)

Immunodeficiency 18AR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Individuals have been described with severe combined immunodeficiency, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial

Refs: 8490660; 15546002

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CD3E variants in ClinVar

7 Conditions Cataloged

Immunodeficiency 18Total: 237

not specifiedTotal: 29

not providedTotal: 27

Inborn genetic diseasesTotal: 22

Severe combined immunodeficiency diseaseTotal: 4

CD3E-related disorderTotal: 3

Immunodeficiency 18, severe combined immunodeficiency variantTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000733.4. 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			2 clinvar	61 clinvar	1 clinvar	64
missense			64 clinvar	5 clinvar	1 clinvar	70
nonsense	5 clinvar	1 clinvar				6
start loss						0
frameshift	5 clinvar	1 clinvar	1 clinvar			7
splice donor/acceptor (+/-2bp)	2 clinvar	7 clinvar	2 clinvar			11
Total	12	9	69	66	2	158

Highest pathogenic variant AF is 0.000022964736

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000733.4	RefSeq	NP_000724.1	8	MANE Select
ENST00000361763.9	Ensembl	ENSP00000354566.4	8	MANE Select
ENST00000528600.1	Ensembl	ENSP00000433975.1	7	Standard
ENST00000528600.2	Ensembl	ENSP00000433975.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Primary immunodeficiency - Homo sapiens (human)
T cell receptor signaling pathway - Homo sapiens (human)
HTLV-I infection - Homo sapiens (human)
Chagas disease (American trypanosomiasis) - Homo sapiens (human)
Th17 cell differentiation - Homo sapiens (human)

Biological Process

positive regulation of cell-matrix adhesion
adaptive immune response
positive regulation of T cell anergy
cell surface receptor signaling pathway
transmembrane receptor protein tyrosine kinase signaling pathway

Molecular Function

transmembrane signaling receptor activity
protein binding
SH3 domain binding
protein kinase binding
receptor signaling complex scaffold activity

Cellular Component

immunological synapse
plasma membrane
integral component of plasma membrane
cell-cell junction
external side of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000361763
Coding exons: 8
Length: 11631
Individuals with no LoFs: 125726
Homozygous LoFs: 0
Heterozygous LoFs: 22
Defined: 125748
p: 0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.304	101	110	0.918	0.00000554	1336
Missense (PolyPhen)		38	36.367	1.0449		457
Synonymous	1.19	31	40.7	0.762	0.00000225	381
Loss of Function	1.79	8	15.6	0.512	8.74e-7	171

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000079	0.000079	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

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). In addition of this role of signal transduction in T-cell activation, CD3E plays an essential role in correct T-cell development. Initiates the TCR-CD3 complex assembly by forming the two heterodimers CD3D/CD3E and CD3G/CD3E. Participates also in internalization and cell surface down- regulation of TCR-CD3 complexes via endocytosis sequences present in CD3E cytosolic region (PubMed:10384095, PubMed:26507128). {ECO:0000269|PubMed:10384095, ECO:0000269|PubMed:15294938, ECO:0000269|PubMed:15546002, ECO:0000269|PubMed:2470098, ECO:0000269|PubMed:26507128, ECO:0000269|PubMed:8490660}.;
Disease: DISEASE: Immunodeficiency 18 (IMD18) [MIM:615615]: An autosomal recessive primary immunodeficiency characterized by onset in infancy or early childhood of recurrent infections. The severity is variable, encompassing both a mild immunodeficiency and severe combined immunodeficiency (SCID), resulting in early death without bone marrow transplantation in some patients. Immunologic work-up of the IMD18 SCID patients shows a T cell-negative, B cell- positive, natural killer (NK) cell-positive phenotype, whereas T- cell development is not impaired in the mild form of IMD18. {ECO:0000269|PubMed:15546002, ECO:0000269|PubMed:8490660}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0410

Intolerance Scores

LoFtool: 0.693
RVIS EVS: 0.37
RVIS percentile EVS: 75.12

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.406

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium