TBL1X

Chr XX-linked

transducin beta like 1 X-linked

Also known as: CHNG8, EBI, SMAP55, TBL1

NCBI Gene: 6907 ENSG00000101849 UniProt: O60907 OMIM: 300196

The protein functions as an F-box-like protein that recruits the ubiquitin/proteasome complex to nuclear receptor-regulated transcription units and plays an essential role in transcription activation by mediating degradation of repressor complexes. Mutations cause X-linked congenital nongoitrous hypothyroidism. This gene is highly constrained against loss-of-function variants, indicating that such variants are likely to be pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene has sequence similarity with members of the WD40 repeat-containing protein family. The WD40 group is a large family of proteins, which appear to have a regulatory function. It is believed that the WD40 repeats mediate protein-protein interactions and members of the family are involved in signal transduction, RNA processing, gene regulation, vesicular trafficking, cytoskeletal assembly and may play a role in the control of cytotypic differentiation. This encoded protein is found as a subunit in corepressor SMRT (silencing mediator for retinoid and thyroid receptors) complex along with histone deacetylase 3 protein. This gene is located adjacent to the ocular albinism gene and it is thought to be involved in the pathogenesis of the ocular albinism with late-onset sensorineural deafness phenotype. Four transcript variants encoding two different isoforms have been found for this gene. This gene is highly similar to the Y chromosome TBL1Y gene. [provided by RefSeq, Nov 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Hypothyroidism, congenital, nongoitrous, 8MIM #301033

X-linked

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Hypothyroidism, congenital, nongoitrous; no ClinGen or GenCC tier

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

0.31

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

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

LoF Constraint?

0.31LOEUF

pLI 0.979

Z-score 4.09

OE 0.12 (0.05–0.31)

Highly constrained

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

Missense Constraint?

2.48Z-score

OE missense 0.56 (0.48–0.64)

138 obs / 247.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.12 (0.05–0.31)

0≤0.351.4

Missense OE?0.56 (0.48–0.64)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 3 / 25.1Missense obs/exp: 138 / 247.8Syn Z: -0.34

Background carrier burden — how many people carry a rare variant somewhere in TBL1X?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 210

359 rare PASS variants

Rare truncating (LoF)

1 in 1,500

24 rare PASS variants

Rare synonymous (reference)

1 in 110

211 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TBL1X. 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 240	1 in 2,000
South Asian	~36k	1 in 300	≈ 1 in 36,000
Remaining (unassigned)	~31k	1 in 320	1 in 910
European (Finnish)	~27k	1 in 410	≈ 1 in 13,000
Admixed American	~23k	1 in 230	1 in 4,400
African / African American	~21k	1 in 210	none seen
East Asian	~20k	1 in 210	≈ 1 in 6,300
Ashkenazi Jewish	~13k	≈ 1 in 6,400	none seen
Middle Eastern	~2,758	1 in 230	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): All 15 coding exons well covered in gnomAD exomes and genomes.? see exons ↓