TXNL4A
protein-codingthioredoxin like 4A, the group of U5 small nuclear ribonucleoprotein
Gene summary
The protein encoded by this gene is a member of the U5 small ribonucleoprotein particle (snRNP), and is involved in pre-mRNA splicing. This protein contains a thioredoxin-like fold and it is expected to interact with multiple proteins. Protein-protein interactions have been observed with the polyglutamine tract-binding protein 1 (PQBP1). Mutations in both the coding region and promoter region of this gene have been associated with Burn-McKeown syndrome, which is a rare disorder characterized by craniofacial dysmorphisms, cardiac defects, hearing loss, and bilateral choanal atresia. A pseudogene of this gene is found on chromosome 2. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2015]
- TXNL4
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~63.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0012064
Submitter: PanelApp Australia
Inheritance Pattern: Unknown
Disease ID:MONDO:0012064
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012064
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012064
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0012064
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0012064
Submitter: ClinGen
The *TXNL4A* gene is located on chromosome 18 at 18p23 and encodes a highly conserved component of the U5 spliceosomal complex that is essential for U4/U6·U5 tri-snRNP assembly, cell cycle progression and pre-mRNA splicing. *TXNL4A* was first reported in relation to autosomal recessive Burn-McKeown syndrome (BMKS) in 2014 (Wieczorek et al., PMID: 25434003). BMKS is a rare multiple congenital anomaly syndrome characterized by bilateral choanal atresia associated with characteristic cranio-facial dysmorphisms and generally normal intelligence. Other phenotypes may include hearing loss, cleft lip/palate, and cardiac defects. At least 10 unique variants (promoter, missense, nonsense, frameshift) that have been reported in 14 probands in four publications (PMIDs: 25434003, 28905882, 32187816, 34713892) are included in this curation. Twelve out of the 14 probands were compound heterozygotes with a 34 bp promoter type 1 deletion (NM_006701.5:c.-222_-189del34) identified on one allele and a loss-of-function variant on the other. This gene-disease relationship is also supported by evidence of functional alteration, and an animal model in Xenopus (PMIDs: 25434003, 32735620, 35893124). In summary, there is definitive evidence to support the relationship between *TXNL4A* and autosomal recessive Burn-McKeown syndrome. 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 GCEP on the meeting date 2/16/2024 (SOP Version 10).
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Craniofacial
Intervention: Audiologic/Otolaryngologic; Cardiovascular
Rationale: As the condition can include prelingual deafness, early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; The condition can involve congenital cardiac anomalies, and awareness may allow early management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TXNL4A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006701.5. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 3 | 3 | ||||
| missense | 10 | 10 | ||||
| nonsense | 1 | 1 | 2 | |||
| start loss | 1 | 1 | ||||
| frameshift | 2 | 2 | 4 | |||
| splice donor/acceptor (+/-2bp) | 3 | 3 | ||||
| Total | 3 | 3 | 14 | 3 | 0 | 23 |
Highest pathogenic variant AF is 0.0000034237196
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006692.1 | 3 | MANE Select | |
| Ensembl | ENSP00000269601.4 | 3 | MANE Select | |
| RefSeq | NP_001290400.1 | 3 | Standard | |
| RefSeq | NP_001292486.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Spliceosome - Homo sapiens (human)
- mRNA Processing
- Metabolism of RNA
- mRNA Splicing - Major Pathway
- mRNA Splicing - Minor Pathway
Biological Process
- spliceosomal complex assembly
- RNA splicing, via transesterification reactions
- mRNA splicing, via spliceosome
- cell cycle
- cell division
Molecular Function
- protein binding
Cellular Component
- nucleus
- nucleoplasm
- spliceosomal complex
- U5 snRNP
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000269601
- Coding exons
- 3
- Length
- 61083
- Individuals with no LoFs
- 125740
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 8
- Defined
- 125748
- p
- 0.0000318
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.77 | 15 | 88.2 | 0.170 | 0.00000487 | 962 |
| Missense (PolyPhen) | 8 | 30.904 | 0.25887 | 337 | ||
| Synonymous | -0.888 | 39 | 32.6 | 1.20 | 0.00000189 | 241 |
| Loss of Function | -0.151 | 6 | 5.61 | 1.07 | 2.38e-7 | 68 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000090 | 0.000087 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000027 | 0.000026 | rare |
| South Asian | 0.000034 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays role in pre-mRNA splicing as component of the U5 snRNP and U4/U6-U5 tri-snRNP complexes that are involved in spliceosome assembly, and as component of the precatalytic spliceosome (spliceosome B complex). {ECO:0000269|PubMed:28781166, ECO:0000305|PubMed:10610776, ECO:0000305|PubMed:26912367}.;
- Disease
- DISEASE: Burn-McKeown syndrome (BMKS) [MIM:608572]: A disease characterized by choanal atresia, sensorineural deafness, cardiac defects, and typical craniofacial dysmorphism consisting of narrow palpebral fissures, coloboma of the lower eyelids, prominent nose with high nasal bridge, short philtrum, cleft lip and/or palate, and large and protruding ears. Intellectual development is normal. {ECO:0000269|PubMed:25434003}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.130
Intolerance Scores
- LoFtool
- 0.447
- RVIS EVS
- -0.08
- RVIS percentile EVS
- 47.79
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.988
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Low | Low |
| Primary Immunodeficiency | Medium | Low | Medium |
| Cancer | Medium | Low | Medium |