TNFRSF14

Chr 1

TNF receptor superfamily member 14

Also known as: ATAR, CD270, HVEA, HVEM, LIGHTR, TR2

NCBI Gene: 8764 ENSG00000157873 UniProt: Q92956 OMIM: 602746

The encoded protein functions as a receptor for multiple ligands including TNF superfamily members and immunoglobulin superfamily members, mediating complex stimulatory and inhibitory immune signaling networks that regulate T-cell activation, survival, and differentiation. Mutations cause autosomal dominant immunodeficiency with susceptibility to viral infections and lymphoproliferation. This gene is highly constrained against loss-of-function variation, suggesting that haploinsufficiency may be poorly tolerated.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the TNF (tumor necrosis factor) receptor superfamily. The encoded protein functions in signal transduction pathways that activate inflammatory and inhibitory T-cell immune response. It binds herpes simplex virus (HSV) viral envelope glycoprotein D (gD), mediating its entry into cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.44

Clinical Summary— TNFRSF14

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.81) — some intolerance to loss-of-function variants.

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ClinVar Variants

34 VUS of 85 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.44LOEUF

pLI 0.808

Z-score 3.00

OE 0.14 (0.06–0.44)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.61Z-score

OE missense 0.87 (0.76–0.99)

151 obs / 173.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.14 (0.06–0.44)

0≤0.351.4

Missense OE?0.87 (0.76–0.99)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 2 / 14.2Missense obs/exp: 151 / 173.7Syn Z: -1.23

This gene — mechanism propensity

0.6066th %ile

GOF

0.7127th %ile

LOF

0.4037th %ile

The highest-scoring mechanism for this gene is gain-of-function.

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.

ClinVar Variant Classifications

85 submitted variants in ClinVar

ClinVar

Classification Summary

VUS34

Likely Benign1

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	34	0	34
Likely Benign	1	0	1
Benign	0	1	1
Total	35	1	36

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

120 pathogenic / likely-pathogenic (of 140) ClinVar copy-number / structural variants overlap TNFRSF14 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →