GeneBe

TBL1XR1

protein-coding

TBL1X/Y related 1, the group of WD repeat domain containing|NCoR/SMRT transcriptional repression complex subunits

Gene summary

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]

MANE transcript

NM_024665.7

Inheritance

AD

ClinVar variants

P:127U:226B:132

Top phenotype

Intellectual developmental disorder, autosomal dominant 41; Pierpont syndrome

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr3:177,019,340-177,228,000

External References & Databases

Ensembl (ENSG00000177565)NCBI Gene (79718)OMIM (608628)HGNC:29529GenCCUniProt (Q9BZK7)AlphaFoldClinVar (TBL1XR1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~208.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

TBL1XR1 has been reported in relation to autosomal dominant complex neurodevelopmental disorders including Pierpont syndrome (PMIDs: 26769062, 30365874, 23499424, 25102098, 30008475, 29777588). At least 6 unique missense variants have been reported in the literature. This gene-disease relationship is supported by case level data. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. In summary, TBL1XR1 is definitively associated with autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Pierpont syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011213

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal dominant 41MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014842

Submitter: Ambry Genetics

Pierpont syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011213

Submitter: G2P

intellectual developmental disorder, autosomal dominant 41STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014842

Submitter: PanelApp Australia

intellectual developmental disorder, autosomal dominant 41STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014842

Submitter: Labcorp Genetics (formerly Invitae)

Pierpont syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011213

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, autosomal dominant 41DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014842

Submitter: G2P

Pierpont syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011213

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 41; Pierpont syndromeAD

Manifestation: Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 9450851; 16007632; 22495309; 23160955; 24891185; 25102098; 26769062Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TBL1XR1 variants in ClinVar

15 Conditions Cataloged
Pierpont syndromeTotal: 463
not providedTotal: 196
Intellectual disability, autosomal dominant 41Total: 71
Inborn genetic diseasesTotal: 51
not specifiedTotal: 44
TBL1XR1-related disorderTotal: 31
Intellectual disabilityTotal: 6
TBL1XR1-related neurodevelopmental disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024665.7. 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.

EffectPLPVUSLBBSum
synonymous
3
clinvar
124
clinvar
1
clinvar
 128
missense
17
clinvar
64
clinvar
211
clinvar
6
clinvar
1
clinvar
 299
nonsense
4
clinvar
7
clinvar
 11
start loss
0
frameshift
16
clinvar
8
clinvar
2
clinvar
 26
splice donor/acceptor (+/-2bp)
3
clinvar
8
clinvar
10
clinvar
 21
Total40872261302485

Highest pathogenic variant AF is 0.0000014399906

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 141 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_024665.7RefSeqNP_078941.214MANE Select
ENST00000457928.7EnsemblENSP00000413251.314MANE Select
NM_001321193.3RefSeqNP_001308122.114Standard
NM_001321194.3RefSeqNP_001308123.114Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • blastocyst hatching
  • response to dietary excess
  • regulation of transcription by RNA polymerase II
  • lipid catabolic process

Molecular Function

  • transcription corepressor activity
  • protein binding
  • beta-catenin binding
  • histone binding
  • transcription regulatory region DNA 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
ENST00000430069
Coding exons
14
Length
178119
Individuals with no LoFs
0
Homozygous LoFs
0
Heterozygous LoFs
0
Defined
0
p
0.00
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense4.20692600.2660.00001203404
Missense (PolyPhen)574.440.0671681045
Synonymous-0.3759489.51.050.00000443942
Loss of Function4.91028.10.000.00000144335

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

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. Plays an essential role in transcription activation mediated by nuclear receptors. Probably acts as integral component of the N-Cor corepressor complex that mediates the recruitment of the 19S proteasome complex, leading to the subsequent proteasomal degradation of N-Cor complex, thereby allowing cofactor exchange, and transcription activation. {ECO:0000269|PubMed:14980219}.;
Disease
DISEASE: Pierpont syndrome (PRPTS) [MIM:602342]: An autosomal dominant syndrome characterized by multiple congenital anomalies, global developmental delay, learning disability, palmar and plantar fat pads, and distinctive facial characteristics, especially when smiling. {ECO:0000269|PubMed:26769062}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mental retardation, autosomal dominant 41 (MRD41) [MIM:616944]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD41 patients manifest delayed psychomotor development, variable severity of intellectual disability, and delayed language. Non-specific dysmorphic features and autistic behavior is observed in some patients. {ECO:0000269|PubMed:22495309, ECO:0000269|PubMed:23160955, ECO:0000269|PubMed:25102098, ECO:0000269|PubMed:27133561}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.254

Intolerance Scores

RVIS EVS
-0.16
RVIS percentile EVS
41.25

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.937

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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