TBL1XR1

Chr 3AD

TBL1X/Y related 1

Also known as: C21, DC42, IRA1, MRD41, TBLR1

NCBI Gene: 79718ENSG00000177565UniProt: Q9BZK7OMIM: 608628

The encoded protein functions as an F-box-like component that recruits the ubiquitin/proteasome complex to nuclear receptor-regulated transcription units and is essential for transcription activation by nuclear receptors. Mutations cause autosomal dominant intellectual developmental disorder and Pierpont syndrome, which involves intellectual disability with distinctive dysmorphic features. This gene is highly constrained against loss-of-function variation (pLI 1.0, LOEUF 0.11), reflecting its critical role in normal development.

OMIMResearchSummary from RefSeq, OMIM, UniProt
MultiplemechanismADLOEUF 0.112 OMIM phenotypes
Clinical Summary— TBL1XR1
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Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
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Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint
0.11LOEUF
pLI 1.000
Z-score 4.91
OE 0.00 (0.00–0.11)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint
4.20Z-score
OE missense 0.27 (0.22–0.33)
69 obs / 259.6 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.00 (0.00–0.11)
0≤0.351.4
Missense OE0.27 (0.22–0.33)
0≤0.61.4
Synonymous OE1.05
0≤1.21.6
LoF obs/exp: 0 / 28.1Missense obs/exp: 69 / 259.6Syn Z: -0.38
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveTBL1XR1-related intellectual disability with autism spectrum disorderLOFAD
definitiveTBL1XR1-related Pierpont syndromeGOFAD
DN
0.2698th %ile
GOF
0.3491th %ile
LOF
0.83top 5%

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

LOFprediction above median · 1 literature citation · LOEUF 0.11
DN1 literature citation

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.

Literature Evidence

DNA dominant-negative effect of this mutation is strongly suspected, since patients with TBL1XR1 deletion and other variants predicting loss of function do not share the same phenotype.PMID:30365874
LOFOur report supports that haploinsufficiency for TBL1XR1 could be implicated in non-ASD autosomal dominant ID.PMID:24891185

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

TBL1XR1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients