GeneBe

THOC6

protein-coding

THO complex subunit 6, the group of WD repeat domain containing|THO complex

Gene summary

This gene encodes a subunit of the multi-protein THO complex, which is involved in coordination between transcription and mRNA processing. The THO complex is a component of the TREX (transcription/export) complex, which is involved in transcription and export of mRNAs. A missense mutation in this gene is associated with a neurodevelopmental disorder called Beaulieu-Boycott-Innes syndrome. [provided by RefSeq, Dec 2016]

Previous symbols:
  • WDR58

MANE transcript

NM_024339.5

Inheritance

AR

ClinVar variants

P:28U:77B:21

Top phenotype

Beaulieu-Boycott-Innes syndrome

gnomAD constraint

pLI —, LoF o/e 0.4

Max pathogenic AF

—

Genomic locus

chr16:3,024,027-3,027,755

External References & Databases

Ensembl (ENSG00000131652)NCBI Gene (79228)OMIM (615403)HGNC:28369GenCCUniProt (Q86W42)AlphaFoldClinVar (THOC6)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~3.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

THOC6-related developmental delay-microcephaly-facial dysmorphism syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013362

Submitter: PanelApp Australia

THOC6-related developmental delay-microcephaly-facial dysmorphism syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013362

Submitter: ClinGen

The THOC6 gene is located on chromosome 16 at 16p13.3 and encodes for a 341-amino acid protein named THOC6, a subunit of the multi-protein THO complex, which is involved in coordination between transcription and mRNA processing. THOC6 was first reported in relation to autosomal recessive Beaulieu-Boycott-Innes Syndrome (BBIS) in 2013 (Beaulieu et al., PMID: 23621916), a neurodevelopmental condition with microcephaly and dysmorphic facial features. 10 variants (missense, nonsense, frameshift) that have been reported in at least 13 probands in 7 publications (PMIDs: 23621916, 26739162, 27102954, 30238602, 30476144, 31421288, 33739554) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (functional alteration evidence, expression-level evidence, mouse model; PMIDs: 23621916, 38388531). Functional alteration evidence in HeLa cells showed an increase in apoptosis when knockdown of THOC6 occurred. Expression evidence showed THOC6 was expressed in zebrafish brains during development. A mouse model showed reduced size, delayed development, and early lethality in the mutant mice compared to the wild-type. In summary, there is definitive evidence supporting the relationship between THOC6 and autosomal recessive BBIS. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date March 15, 2024 (SOP Version 10).

THOC6-related developmental delay-microcephaly-facial dysmorphism syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013362

Submitter: G2P

THOC6-related developmental delay-microcephaly-facial dysmorphism syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013362

Submitter: Labcorp Genetics (formerly Invitae)

THOC6-related developmental delay-microcephaly-facial dysmorphism syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013362

Submitter: Ambry Genetics

THOC6-related developmental delay-microcephaly-facial dysmorphism syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013362

Submitter: Orphanet

Clinical Genomic Database (CGD)

Beaulieu-Boycott-Innes syndromeAR

Manifestation: Cardiovascular; Craniofacial; Dental; Genitourinary; Neurologic; Renal

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 23621916; 26739162; 27102954; 30476144Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to THOC6 variants in ClinVar

7 Conditions Cataloged
Inborn genetic diseasesTotal: 69
not providedTotal: 35
THOC6-related developmental delay-microcephaly-facial dysmorphism syndromeTotal: 33
THOC6-related disorderTotal: 11
not specifiedTotal: 4
Intellectual disabilityTotal: 4
Dystonia, early-onset, and/or spastic paraplegiaTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024339.5. 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
1
clinvar
17
clinvar
1
clinvar
 19
missense
1
clinvar
5
clinvar
70
clinvar
3
clinvar
 79
nonsense
3
clinvar
6
clinvar
 9
start loss
0
frameshift
3
clinvar
5
clinvar
1
clinvar
 9
splice donor/acceptor (+/-2bp)
1
clinvar
4
clinvar
5
clinvar
 10
Total82077201126

Highest pathogenic variant AF is 0.0003643472

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_024339.5RefSeqNP_077315.213MANE Select
ENST00000326266.13EnsemblENSP00000326531.813MANE Select
NM_001142350.3RefSeqNP_001135822.112Standard
NM_001347703.2RefSeqNP_001334632.112Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • RNA transport - Homo sapiens (human)
  • Gene expression (Transcription)
  • RNA Polymerase II Transcription
  • Metabolism of RNA
  • Cleavage of Growing Transcript in the Termination Region

Biological Process

  • RNA export from nucleus
  • mRNA export from nucleus
  • apoptotic process
  • central nervous system development
  • RNA splicing

Molecular Function

  • RNA binding

Cellular Component

  • transcription export complex
  • THO complex
  • THO complex part of transcription export complex
  • nuclear chromosome, telomeric region
  • nucleus

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000326266
Coding exons
13
Length
3729
Individuals with no LoFs
125714
Homozygous LoFs
0
Heterozygous LoFs
34
Defined
125748
p
0.000135
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.4022232071.080.00001282189
Missense (PolyPhen)5455.9260.96557646
Synonymous-1.4710183.91.200.00000527697
Loss of Function2.811025.20.3970.00000131256

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000190.00018rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian0.000490.00049rare
Finnish00.0absent
European (Non-Finnish)0.000150.00015rare
South Asian0.000130.00013rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Acts as component of the THO subcomplex of the TREX complex which is thought to couple mRNA transcription, processing and nuclear export, and which specifically associates with spliced mRNA and not with unspliced pre-mRNA. TREX is recruited to spliced mRNAs by a transcription-independent mechanism, binds to mRNA upstream of the exon-junction complex (EJC) and is recruited in a splicing- and cap-dependent manner to a region near the 5' end of the mRNA where it functions in mRNA export to the cytoplasm via the TAP/NFX1 pathway. The TREX complex is essential for the export of Kaposi's sarcoma-associated herpesvirus (KSHV) intronless mRNAs and infectious virus production. Plays a role in apoptosis negative control involved in brain development. {ECO:0000269|PubMed:15833825, ECO:0000269|PubMed:15998806, ECO:0000269|PubMed:17190602, ECO:0000269|PubMed:18974867, ECO:0000269|PubMed:23621916}.;
Disease
DISEASE: Beaulieu-Boycott-Innes syndrome (BBIS) [MIM:613680]: An autosomal recessive neurodevelopmental disorder characterized by delayed development, moderate intellectual disability, and dysmorphic facial features. Other developmental anomalies, such as cardiac and renal defects, may also occur. {ECO:0000269|PubMed:23621916}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.110

Intolerance Scores

LoFtool
0.904
RVIS EVS
-1.11
RVIS percentile EVS
6.72

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
H
Indispensability pred.
E
Indispensability score
0.758

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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