TLR7

Chr XXLRXLD

toll like receptor 7

ENSG00000196664 UniProt: Q9NYK1 OMIM: 300365

TLR7 encodes an endosomal receptor that recognizes single-stranded RNA from viruses and activates innate immune responses by triggering cytokine and interferon production. Mutations cause X-linked immunodeficiency with increased susceptibility to severe COVID-19 infections and X-linked systemic lupus erythematosus. The gene is highly constrained against loss-of-function mutations and shows both X-linked recessive and dominant inheritance patterns.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Endosomal receptor that plays a key role in innate and adaptive immunity (PubMed:14976261, PubMed:32433612). Controls host immune response against pathogens through recognition of uridine-containing single strand RNAs (ssRNAs) of viral origin or guanosine analogs (PubMed:12738885, PubMed:27742543, PubMed:31608988, PubMed:32706371, PubMed:35477763). Upon binding to agonists, undergoes dimerization that brings TIR domains from the two molecules into direct contact, leading to the recruitment of TIR-containing downstream adapter MYD88 through homotypic interaction (PubMed:27742543). In turn, the Myddosome signaling complex is formed involving IRAK4, IRAK1, TRAF6, TRAF3 leading to activation of downstream transcription factors NF-kappa-B and IRF7 to induce pro-inflammatory cytokines and interferons, respectively (PubMed:27742543, PubMed:32706371). In plasmacytoid dendritic cells, RNASET2 endonuclease cooperates with PLD3 or PLD4 5'->3' exonucleases to process RNA and release 2',3'-cyclic guanosine monophosphate (2',3'-cGMP) and cytidine-rich RNA fragments that occupy TLR7 ligand-binding pockets and trigger a signaling-competent state

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Immunodeficiency 74, COVID19-related, X-linkedMIM #301051

XLR

Systemic lupus erythematosus 17MIM #301080

XLD

Clinical highlights

Gene–disease validity (ClinGen)

Moderate · systemic lupus erythematosus 17 · XL · ClinGen 2024

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

747

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.30

LOEUF· LoF intol.

—

Mechanism

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — X-linked: males carry a single copy

LoF Constraint?

0.30LOEUF

pLI 0.979

Z-score 3.80

OE 0.10 (0.04–0.30)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.01Z-score

OE missense 0.56 (0.50–0.63)

205 obs / 367.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.10 (0.04–0.30)

0≤0.351.4

Missense OE?0.56 (0.50–0.63)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 2 / 20.7Missense obs/exp: 205 / 367.6Syn Z: -0.53

Background carrier burden — how many people carry a rare variant somewhere in TLR7?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 180

546 rare PASS variants

Rare truncating (LoF)

1 in 8,000

35 rare PASS variants

Rare synonymous (reference)

1 in 170

318 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TLR7. 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)	~561k	1 in 200	1 in 28,000
South Asian	~36k	1 in 130	none seen
Remaining (unassigned)	~31k	1 in 190	1 in 3,800
European (Finnish)	~27k	1 in 580	1 in 3,500
Admixed American	~23k	1 in 160	≈ 1 in 5,400
African / African American	~21k	1 in 88	≈ 1 in 5,200
East Asian	~20k	1 in 200	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 350	≈ 1 in 13,000
Middle Eastern	~2,758	1 in 230	≈ 1 in 2,800

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 2 coding exons well covered in gnomAD exomes and genomes.? see exons ↓