SETX

senataxin, the group of UPF1 like RNA helicases|SSU processome

Basic information

Region (hg38): 9:132261355-132354986

Previous symbols: [ "ALS4", "SCAR1" ]

Links

ENSG00000107290 ∙ NCBI:23064 ∙ OMIM:608465 ∙ HGNC:445 ∙ Uniprot:Q7Z333 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (Supportive), mode of inheritance: AR
• amyotrophic lateral sclerosis type 4 (Supportive), mode of inheritance: AD
• amyotrophic lateral sclerosis type 4 (Definitive), mode of inheritance: AD
• spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (Definitive), mode of inheritance: AR
• amyotrophic lateral sclerosis type 4 (Strong), mode of inheritance: AD
• spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (Strong), mode of inheritance: AR
• distal hereditary motor neuropathy (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2; Amyotrophic lateral sclerosis 4, juvenile; Ataxia with oculomotor apraxia, type 2	AD/AR	General	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	Neurologic	7214250; 15106121; 14770181; 15732101; 16717225; 16644229; 17096168; 18405395; 18663494; 19141356; 19569000; 19593598; 19696032; 19727998; 19893583; 21438761; 22088787; 22341623; 22577233; 23111195

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SETX gene.

• not provided (595 variants)
• Amyotrophic lateral sclerosis type 4;Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (485 variants)
• Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (406 variants)
• Amyotrophic lateral sclerosis type 4 (382 variants)
• Inborn genetic diseases (363 variants)
• Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2;Amyotrophic lateral sclerosis type 4 (345 variants)
• not specified (132 variants)
• Hereditary spastic paraplegia (72 variants)
• SETX-related condition (33 variants)
• Amyotrophic lateral sclerosis (11 variants)
• Amyotrophic Lateral Sclerosis, Dominant (6 variants)
• Charcot-Marie-Tooth disease (5 variants)
• See cases (4 variants)
• Spastic ataxia (3 variants)
• Distal spinal muscular atrophy (3 variants)
• Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia (3 variants)
• Frontotemporal dementia (3 variants)
• Neuronopathy, distal hereditary motor, autosomal dominant (1 variants)
• Cerebral palsy (1 variants)
• SETX-Related Disorders (1 variants)
• 7 conditions (1 variants)
• Dystonic disorder;Mental deterioration (1 variants)
• Tay-Sachs disease (1 variants)
• Spastic paraplegia (1 variants)
• Abnormal central motor function (1 variants)
• Cerebellar ataxia (1 variants)
• - (1 variants)
• Charcot-Marie-Tooth disease type 2 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SETX gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			12	180	11	203
missense	6	12	581	49	44	692
nonsense	10	10	1			21
start loss						0
frameshift	18	15	10			43
inframe indel		2	24	2		28
splice donor/acceptor (+/-2bp)	1	6				7
splice region		1	23	14	4	42
non coding			41	108	99	248
Total	35	45	669	339	154

Highest pathogenic variant AF is 0.0000394

Variants in SETX

This is a list of pathogenic ClinVar variants found in the SETX region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
9-132261486-C-T		Amyotrophic lateral sclerosis type 4 • Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	Uncertain significance (Jan 13, 2018)
9-132261600-A-G		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 • Amyotrophic lateral sclerosis type 4	Uncertain significance (Jan 13, 2018)
9-132261629-A-C		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 • Amyotrophic lateral sclerosis type 4	Uncertain significance (Jan 13, 2018)
9-132261661-ATT-A		Amyotrophic Lateral Sclerosis, Dominant • Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	Uncertain significance (Jun 14, 2016)
9-132261733-A-G		Amyotrophic lateral sclerosis type 4 • Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	Benign/Likely benign (Jan 13, 2018)
9-132261855-A-T		Amyotrophic lateral sclerosis type 4 • Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	Uncertain significance (Jan 13, 2018)
9-132261952-A-G		Amyotrophic lateral sclerosis type 4 • Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	Uncertain significance (Jan 12, 2018)
9-132261977-T-C		Amyotrophic lateral sclerosis type 4 • Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	Benign (Feb 08, 2023)
9-132262007-A-G		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 • Amyotrophic lateral sclerosis type 4	Benign/Likely benign (Jan 12, 2018)
9-132262049-T-C		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 • Amyotrophic lateral sclerosis type 4	Conflicting classifications of pathogenicity (Jan 13, 2018)
9-132262103-T-A		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 • Amyotrophic lateral sclerosis type 4	Uncertain significance (Jan 12, 2018)
9-132262173-G-GT		Amyotrophic Lateral Sclerosis, Dominant • Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	Uncertain significance (Jun 14, 2016)
9-132262223-C-T		Amyotrophic lateral sclerosis type 4 • Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	Uncertain significance (Jan 17, 2018)
9-132262224-G-A		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 • Amyotrophic lateral sclerosis type 4	Uncertain significance (Jan 12, 2018)
9-132262237-T-C		Amyotrophic lateral sclerosis type 4 • Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	Uncertain significance (Jan 12, 2018)
9-132262252-A-G		Amyotrophic lateral sclerosis type 4 • Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	Uncertain significance (Jan 12, 2018)
9-132262436-C-T		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 • Amyotrophic lateral sclerosis type 4	Conflicting classifications of pathogenicity (Jan 12, 2018)
9-132262439-G-A		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 • Amyotrophic lateral sclerosis type 4	Uncertain significance (Jan 13, 2018)
9-132262517-T-C		Amyotrophic lateral sclerosis type 4 • Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	Uncertain significance (Jan 12, 2018)
9-132262526-G-A		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 • Amyotrophic lateral sclerosis type 4	Uncertain significance (Jan 13, 2018)
9-132262539-C-A		Amyotrophic lateral sclerosis type 4 • Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	Benign/Likely benign (Feb 08, 2023)
9-132262551-T-C		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 • Amyotrophic lateral sclerosis type 4	Uncertain significance (Jan 12, 2018)
9-132262705-C-T		Amyotrophic lateral sclerosis type 4 • Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	Uncertain significance (Jan 12, 2018)
9-132262716-T-C		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 • Amyotrophic lateral sclerosis type 4	Uncertain significance (Jan 13, 2018)
9-132262745-T-C		Amyotrophic lateral sclerosis type 4 • Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	Uncertain significance (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SETX	protein_coding	protein_coding	ENST00000224140	24	93630

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.955	0.0452	125661	0	87	125748	0.000346

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.112	1392	1.38e+3	1.01	0.0000736	17701
Missense in Polyphen		338	468.32	0.72172		5957
Synonymous	-1.95	556	500	1.11	0.0000273	5045
Loss of Function	7.45	21	102	0.205	0.00000564	1368

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000970	0.000970
Ashkenazi Jewish	0.00	0.00
East Asian	0.000163	0.000163
Finnish	0.000416	0.000277
European (Non-Finnish)	0.000309	0.000308
Middle Eastern	0.000163	0.000163
South Asian	0.000633	0.000621
Other	0.000654	0.000652

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Probable RNA/DNA helicase involved in diverse aspects of RNA metabolism and genomic integrity. Plays a role in transcription regulation by its ability to modulate RNA Polymerase II (Pol II) binding to chromatin and through its interaction with proteins involved in transcription (PubMed:19515850, PubMed:21700224). Contributes to the mRNA splicing efficiency and splice site selection (PubMed:19515850). Required for the resolution of R-loop RNA-DNA hybrid formation at G-rich pause sites located downstream of the poly(A) site, allowing XRN2 recruitment and XRN2-mediated degradation of the downstream cleaved RNA and hence efficient RNA polymerase II (RNAp II) transcription termination (PubMed:19515850, PubMed:21700224, PubMed:26700805). Required for the 3' transcriptional termination of PER1 and CRY2, thus playing an important role in the circadian rhythm regulation (By similarity). Involved in DNA double-strand breaks damage response generated by oxidative stress (PubMed:17562789). In association with RRP45, targets the RNA exosome complex to sites of transcription-induced DNA damage (PubMed:24105744). Plays a role in the development and maturation of germ cells: essential for male meiosis, acting at the interface of transcription and meiotic recombination, and in the process of gene silencing during meiotic sex chromosome inactivation (MSCI) (By similarity). May be involved in telomeric stability through the regulation of telomere repeat-containing RNA (TERRA) transcription (PubMed:21112256). Plays a role in neurite outgrowth in hippocampal cells through FGF8-activated signaling pathways. Inhibits retinoic acid-induced apoptosis (PubMed:21576111). {ECO:0000250|UniProtKB:A2AKX3, ECO:0000269|PubMed:17562789, ECO:0000269|PubMed:19515850, ECO:0000269|PubMed:21112256, ECO:0000269|PubMed:21576111, ECO:0000269|PubMed:21700224, ECO:0000269|PubMed:24105744, ECO:0000269|PubMed:26700805}.
• Disease: DISEASE: Spinocerebellar ataxia, autosomal recessive, 1 (SCAR1) [MIM:606002]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR1 is an autosomal recessive form associated with peripheral neuropathy and elevated serum alpha- fetoprotein, immunoglobulins and, less commonly, creatine kinase levels. Some SCAR1 patients manifest oculomotor apraxia. {ECO:0000269|PubMed:14770181, ECO:0000269|PubMed:16644229, ECO:0000269|PubMed:16717225, ECO:0000269|PubMed:17096168, ECO:0000269|PubMed:23566282, ECO:0000269|PubMed:23786967, ECO:0000269|PubMed:23941260, ECO:0000269|PubMed:24105744}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Amyotrophic lateral sclerosis 4 (ALS4) [MIM:602433]: A form of amyotrophic lateral sclerosis with childhood- or adolescent-onset, and characterized by slow disease progression and the sparing of bulbar and respiratory muscles. Amyotrophic lateral sclerosis is a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. {ECO:0000269|PubMed:14770181, ECO:0000269|PubMed:15106121, ECO:0000269|PubMed:21190393, ECO:0000269|PubMed:24105744, ECO:0000269|PubMed:24244371}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Interactome of polycomb repressive complex 2 (PRC2) (Consensus)

Recessive Scores

• pRec: 0.413

Intolerance Scores

• loftool: 0.0245
• rvis_EVS: -0.14
• rvis_percentile_EVS: 42.88

Haploinsufficiency Scores

• pHI: 0.0742
• hipred: N
• hipred_score: 0.233
• ghis: 0.592

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.763

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Setx
• Phenotype: cellular phenotype; homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype; immune system phenotype; reproductive system phenotype; hematopoietic system phenotype

Gene ontology

• Biological process: MAPK cascade;double-strand break repair;DNA recombination;DNA-templated transcription, termination;termination of RNA polymerase II transcription;mRNA splice site selection;RNA processing;cellular response to DNA damage stimulus;spermatogenesis;circadian rhythm;fibroblast growth factor receptor signaling pathway;positive regulation of neuron projection development;DNA duplex unwinding;positive regulation of RNA splicing;cellular response to oxidative stress;negative regulation of apoptotic process;protein kinase B signaling;cellular response to fibroblast growth factor stimulus;positive regulation of transcription by RNA polymerase II;positive regulation of DNA-templated transcription, termination;cellular response to hydrogen peroxide;cellular response to retinoic acid;positive regulation of DNA-templated transcription, initiation;positive regulation of termination of RNA polymerase II transcription, poly(A)-coupled
• Cellular component: nuclear chromosome;chromosome, telomeric region;nucleus;nucleoplasm;nucleolus;cytoplasm;nuclear body;axon;growth cone;intercellular bridge
• Molecular function: transcription termination site sequence-specific DNA binding;DNA binding;DNA helicase activity;RNA binding;protein binding;ATP binding;identical protein binding