TBL1XR1

Chr 3AD

TBL1X/Y related 1

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

NCBI Gene: 79718 ENSG00000177565 UniProt: Q9BZK7 OMIM: 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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is a member of the WD40 repeat-containing gene family and shares sequence similarity with transducin (beta)-like 1X-linked (TBL1X). The protein encoded by this gene is thought to be a component of both nuclear receptor corepressor (N-CoR) and histone deacetylase 3 (HDAC 3) complexes, and is required for transcriptional activation by a variety of transcription factors. Mutations in these gene have been associated with some autism spectrum disorders, and one finding suggests that haploinsufficiency of this gene may be a cause of intellectual disability with dysmorphism. Mutations in this gene as well as recurrent translocations involving this gene have also been observed in some tumors. [provided by RefSeq, Mar 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal dominant 41MIM #616944

Pierpont syndromeMIM #602342

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · complex neurodevelopmental disorder · AD · ClinGen 2020

Interpreting a novel variant

Curated mechanisms (Gene2Phenotype) include both loss of function and gain of function. Which applies is variant-dependent — do not assume a null variant is, or isn’t, the pathogenic class without checking the specific variant.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.11

LOEUF· LoF intol.

Multiple*

Mechanism· G2P

📖

GeneReview available — TBL1XR1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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 OE?0.00 (0.00–0.11)

0≤0.351.4

Missense OE?0.27 (0.22–0.33)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 0 / 28.1Missense obs/exp: 69 / 259.6Syn Z: -0.38

Background carrier burden — how many people carry a rare variant somewhere in TBL1XR1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 550

269 rare PASS variants

Rare truncating (LoF)

1 in 11,000

15 rare PASS variants

Rare synonymous (reference)

1 in 280

230 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TBL1XR1. 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 510	1 in 10,000
South Asian	~43k	1 in 540	1 in 2,000
Remaining (unassigned)	~30k	1 in 810	none seen
European (Finnish)	~27k	1 in 1,700	≈ 1 in 25,000
Admixed American	~22k	1 in 570	≈ 1 in 6,300
African / African American	~21k	1 in 420	≈ 1 in 21,000
East Asian	~20k	1 in 520	≈ 1 in 9,200
Ashkenazi Jewish	~13k	1 in 2,100	none seen
Middle Eastern	~2,884	≈ 1 in 1,400	none seen

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): 11 of 14 coding exons well covered in gnomAD exomes; exons 3, 10, 15 marginal. Genomes: all 14.? see exons ↓

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.

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

📖

GeneReview available — TBL1XR1

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Medullary Thyroid CancerInfantile MyofibromatosisInfantile Fibrosarcoma

A Study of Oral LOXO-292 (Selpercatinib) in Pediatric Participants With Advanced Solid or Primary Central Nervous System (CNS) Tumors

ACTIVE NOT RECRUITING

NCT03899792Phase PHASE1, PHASE2Eli Lilly and CompanyStarted 2019-06-13

Selpercatinib

Non-Small Cell Lung CancerMedullary Thyroid CancerColon Cancer

A Study of Selpercatinib (LOXO-292) in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRETTO-001)

ACTIVE NOT RECRUITING

NCT03157128Phase PHASE1, PHASE2Eli Lilly and CompanyStarted 2017-05-02

LOXO-292

Clinical Literature

Open Research Assistant →

Landmark / reviewRecent case evidence

Full-Text Mentions

NLP-detected gene mentions in article bodies · via PubTator3

PubTator3

Arsenic trioxide induces proteasome dependent TBLR1-RARalpha degradation to improve leukemia eradication through cell differentiation enhancement

Chen Y et al.·J Cancer

2022