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…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.44

LOEUF

GOF

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in TNFRSF14?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

389 rare PASS variants

Rare truncating (LoF)

1 in 1,300

52 rare PASS variants

Rare synonymous (reference)

1 in 240

158 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TNFRSF14. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 240	1 in 2,500
South Asian	~43k	1 in 110	1 in 3,400
Remaining (unassigned)	~30k	1 in 140	1 in 740
European (Finnish)	~27k	1 in 550	≈ 1 in 24,000
Admixed American	~22k	1 in 120	1 in 300
African / African American	~21k	1 in 210	1 in 2,200
East Asian	~20k	1 in 230	1 in 950
Ashkenazi Jewish	~13k	1 in 920	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 140	1 in 560

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 8 coding exons well covered in gnomAD exomes and genomes.? see exons ↓