CD247

Chr 1AR

CD247 molecule

Also known as: CD3-ZETA, CD3H, CD3Q, CD3Z, CD3ZETA, IMD25, T3Z, TCRZ

NCBI Gene: 919 ENSG00000198821 UniProt: P20963 OMIM: 186780

The CD247 protein is the T-cell receptor zeta chain that forms part of the TCR-CD3 complex on T-lymphocytes and transmits antigen recognition signals across the cell membrane through phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs). Mutations cause immunodeficiency 25, an autosomal recessive disorder affecting adaptive immune response. The gene shows tolerance to loss-of-function variants (pLI 0.017, LOEUF 0.824), consistent with recessive inheritance requiring biallelic mutations for disease.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.821 OMIM phenotype

Clinical Summary— CD247

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Gene-Disease Validity (ClinGen)

immunodeficiency 25 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.82LOEUF

pLI 0.017

Z-score 2.01

OE 0.39 (0.20–0.82)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.31Z-score

OE missense 1.09 (0.93–1.28)

104 obs / 95.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.39 (0.20–0.82)

0≤0.351.4

Missense OE?1.09 (0.93–1.28)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 5 / 12.8Missense obs/exp: 104 / 95.5Syn Z: 0.65

This gene — mechanism propensity

0.87top 5%

GOF

0.76top 25%

LOF

0.1994th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.