CD3D

protein-coding

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

Gene summary

The protein encoded by this gene is part of the T-cell receptor/CD3 complex (TCR/CD3 complex) and is involved in T-cell development and signal transduction. The encoded membrane protein represents the delta subunit of the CD3 complex, and along with four other CD3 subunits, binds either TCR alpha/beta or TCR gamma/delta to form the TCR/CD3 complex on the surface of T-cells. Defects in this gene are a cause of severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-positive/NK-cell-positive (SCIDBNK). Two transcript variants encoding different isoforms have been found for this gene. Other variants may also exist, but the full-length natures of their transcripts has yet to be defined. [provided by RefSeq, Feb 2009]

Previous symbols:

MANE transcript

NM_000732.6

Inheritance

ClinVar variants

P:17U:72B:56

Top phenotype

Immunodeficiency 19, severe combined

gnomAD constraint

pLI —, LoF o/e 0.78

Max pathogenic AF

—

Genomic locus

chr11:118,334,537-118,342,705

External References & Databases

Ensembl (ENSG00000167286)

Transcript & Mutation Effects

hg38 • Region Span ~8.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency 19STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014280

Submitter: Labcorp Genetics (formerly Invitae)

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

Inheritance Pattern: AR

Disease ID:MONDO:0015703

Submitter: Orphanet

immunodeficiency 19DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014280

Submitter: ClinGen

CD3D was first reported in relation to autosomal recessive immunodeficiency 19 in 2003 (Dadi et al., PMID: 14602880). Immunodeficiency 19 is a T-B+NK+ severe combined immunodeficiency (SCID). Six variants (nonsense, splice site, and intronic) that have been reported in 6 probands in 6 publications are included in this curation (PMID: 14602880, 15546002, 15729559, 28916186, 33628209, 21926461). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Affected individuals typically present in infancy with severe, recurrent infections and very low T cell counts. Hypomorphic phenotypes including Omenn syndrome and leaky SCID with a selective block in alpha beta but not in gamma delta T cell development have also been reported (PMID: 33628209, 21926461). The mechanism of pathogenicity is loss of function. This gene-disease association is supported by expression studies, protein interactions, functional assays, an animal model, and a rescue assay (PMIDs: 18853439, 31461748, 34249896, 15546002, 9135151). CD3D is expressed in lymphoid tissues and encodes the delta chain of the T-cell receptor (TCR) complex (PMID: 18853439). The TCR is made up of multiple other CD3 chains including epsilon (CD3E gene), gamma (CD3G gene), and zeta (CD247) (PMID: 31461748). We have previously established that these three genes; CD3E, CD3G, and CD247; are definitively associated with severe combined immunodeficiency. A Jurkat cell line with knocked down CD3D shows impaired cell surface expression of TCR complexes, and patient T cells with a CD3D homozygous loss of function variant have blocked T cell differentiation (PMID: 34249896, 15546002). CD3D knockout mice show abnormal alpha beta T cell development which is restored with a CD3D transgene (PMID: 9135151). In summary, CD3D is definitively associated with autosomal recessive immunodeficiency 19. 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 April 21, 2022 (SOP Version 8).

Clinical Genomic Database (CGD)

Immunodeficiency 19, severe combinedAR

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; BMT has been reported

Refs: 14602880; 15546002

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CD3D variants in ClinVar

6 Conditions Cataloged

Immunodeficiency 19Total: 190

Inborn genetic diseasesTotal: 25

not providedTotal: 12

not specifiedTotal: 10

CD3D-related disorderTotal: 3

Severe combined immunodeficiency diseaseTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000732.6. 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	53 clinvar		55
missense			67 clinvar	3 clinvar		70
nonsense	5 clinvar	1 clinvar	2 clinvar			8
start loss						0
frameshift	5 clinvar	1 clinvar	1 clinvar			7
splice donor/acceptor (+/-2bp)		5 clinvar				5
Total	10	7	72	56	0	145

Highest pathogenic variant AF is 0.000053284428

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000732.6	RefSeq	NP_000723.1	5	MANE Select
ENST00000300692.9	Ensembl	ENSP00000300692.4	5	MANE Select
NM_001040651.2	RefSeq	NP_001035741.1	4	Standard
ENST00000392884.2	Ensembl	ENSP00000376622.2	4	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

adaptive immune response
cell surface receptor signaling pathway
T cell differentiation
positive thymic T cell selection
positive regulation of transcription by RNA polymerase II

Molecular Function

transcription coactivator activity
transmembrane signaling receptor activity
protein homodimerization activity
protein heterodimerization activity

Cellular Component

cytoplasm
plasma membrane
external side of plasma membrane
integral component of membrane
clathrin-coated vesicle membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000300692
Coding exons: 5
Length: 3791
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125748
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.00952	92	92.3	0.997	0.00000531	1095
Missense (PolyPhen)		26	28.396	0.91563		364
Synonymous	0.0574	36	36.4	0.988	0.00000217	355
Loss of Function	0.602	7	8.94	0.783	5.54e-7	94

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

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, CD3D plays an essential role in thymocyte differentiation. Indeed, participates in correct intracellular TCR-CD3 complex assembly and surface expression. In absence of a functional TCR-CD3 complex, thymocytes are unable to differentiate properly. Interacts with CD4 and CD8 and thus serves to establish a functional link between the TCR and coreceptors CD4 and CD8, which is needed for activation and positive selection of CD4 or CD8 T-cells(PubMed:12215456). {ECO:0000269|PubMed:12215456, ECO:0000269|PubMed:12507424, ECO:0000269|PubMed:2470098}.;
Disease: DISEASE: Immunodeficiency 19 (IMD19) [MIM:615617]: An autosomal recessive form of severe combined immunodeficiency characterized by onset in early infancy of recurrent bacterial, viral, and fungal infections. Patients usually have chronic diarrhea, recurrent respiratory infections, and failure to thrive. Immunologic work-up shows a T-cell negative, B-cell positive, NK- cell positive phenotype. {ECO:0000269|PubMed:14602880, ECO:0000269|PubMed:15546002, ECO:0000269|PubMed:21883749}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.382

Intolerance Scores

LoFtool: 0.953
RVIS EVS: -0.21
RVIS percentile EVS: 38.28

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0142

Gene Damage Prediction

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