TBL1X

protein-coding

transducin beta like 1 X-linked, the group of WD repeat domain containing|NCoR/SMRT transcriptional repression complex subunits

Gene summary

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]

Previous symbols:

TBL1

MANE transcript

NM_005647.4

Inheritance

ClinVar variants

P:2U:161B:12

Top phenotype

Hypothyroidism, congenital, nongoitrous, 8

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chrX:9,463,320-9,741,037

External References & Databases

Ensembl (ENSG00000101849)

Transcript & Mutation Effects

hg38 • Region Span ~277.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypothyroidism, congenital, nongoitrous, 8LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0026731

Submitter: Labcorp Genetics (formerly Invitae)

hypothyroidism, congenital, nongoitrous, 8STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0026731

Submitter: PanelApp Australia

hypothyroidism, congenital, nongoitrous, 8STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0026731

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Hypothyroidism, congenital, nongoitrous, 8XL

Manifestation: Audiologic/Otolaryngologic; Endocrine

Intervention: Audiologic/Otolaryngologic; Endocrine

Rationale: Individuals may have hearing loss, and early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Individuals have been described with hypothyroidism, and awareness may allow management (eg, with thyroid hormone replacement)

Refs: 27603907; 30591955

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TBL1X variants in ClinVar

6 Conditions Cataloged

Inborn genetic diseasesTotal: 49

not providedTotal: 38

Hypothyroidism, congenital, nongoitrous, 8Total: 8

TBL1X-related disorderTotal: 5

Congenital hypothyroidismTotal: 3

not specifiedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005647.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			14 clinvar	6 clinvar	3 clinvar	23
missense		1 clinvar	122 clinvar	2 clinvar	1 clinvar	126
nonsense		1 clinvar	7 clinvar			8
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			18 clinvar			18
Total	0	2	161	8	4	175

Highest pathogenic variant AF is 9.118904e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005647.4	RefSeq	NP_005638.1	15	MANE Select
ENST00000645353.2	Ensembl	ENSP00000496215.1	15	MANE Select
NM_001139466.1	RefSeq	NP_001132938.1	15	Standard
NM_001139467.1	RefSeq	NP_001132939.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Wnt signaling pathway - Homo sapiens (human)
Ectoderm Differentiation
Disease
Signal Transduction
Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha)

Biological Process

negative regulation of transcription by RNA polymerase II
regulation of transcription by RNA polymerase II
proteolysis
sensory perception of sound
histone deacetylation

Molecular Function

transcription corepressor activity
protein binding
beta-catenin binding
protein C-terminus binding
transcription factor binding

Cellular Component

histone deacetylase complex
nucleus
nucleoplasm
transcriptional repressor complex
mitotic spindle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000217964
Coding exons: 15
Length: 256446
Individuals with no LoFs: 125741
Homozygous LoFs: 2
Heterozygous LoFs: 3
Defined: 125746
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.48	138	248	0.557	0.0000211	3774
Missense (PolyPhen)		17	68.15	0.24945		1129
Synonymous	-0.338	118	113	1.04	0.0000115	1113
Loss of Function	4.09	3	25.1	0.119	0.00000216	362

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000037	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000074	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000037	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: F-box-like protein involved in the recruitment of the ubiquitin/19S proteasome complex to nuclear receptor-regulated transcription units (PubMed:14980219). Plays an essential role in transcription activation mediated by nuclear receptors. Probably acts as integral component of corepressor complexes that mediates the recruitment of the 19S proteasome complex, leading to the subsequent proteasomal degradation of transcription repressor complexes, thereby allowing cofactor exchange (PubMed:21240272). {ECO:0000269|PubMed:14980219, ECO:0000269|PubMed:21240272}.;

Recessive Scores

pRec: 0.368

Intolerance Scores

LoFtool: 0.0803
RVIS EVS: -0.82
RVIS percentile EVS: 11.77

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.943

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium