ATXN1

protein-coding

ataxin 1

Gene summary

The autosomal dominant cerebellar ataxias (ADCA) are a heterogeneous group of neurodegenerative disorders characterized by progressive degeneration of the cerebellum, brain stem and spinal cord. Clinically, ADCA has been divided into three groups: ADCA types I-III. ADCAI is genetically heterogeneous, with five genetic loci, designated spinocerebellar ataxia (SCA) 1, 2, 3, 4 and 6, being assigned to five different chromosomes. ADCAII, which always presents with retinal degeneration (SCA7), and ADCAIII often referred to as the `pure' cerebellar syndrome (SCA5), are most likely homogeneous disorders. Several SCA genes have been cloned and shown to contain CAG repeats in their coding regions. ADCA is caused by the expansion of the CAG repeats, producing an elongated polyglutamine tract in the corresponding protein. The expanded repeats are variable in size and unstable, usually increasing in size when transmitted to successive generations. The function of the ataxins is not known. This locus has been mapped to chromosome 6, and it has been determined that the diseased allele contains 40-83 CAG repeats, compared to 6-39 in the normal allele, and is associated with spinocerebellar ataxia type 1 (SCA1). Alternative splicing results in multiple transcript variants, with one variant encoding multiple distinct proteins, ATXN1 and Alt-ATXN1, due to the use of overlapping alternate reading frames. [provided by RefSeq, Nov 2017]

Previous symbols:

SCA1

MANE transcript

NM_001128164.2

Inheritance

ClinVar variants

U:111B:56

Top phenotype

Spinocerebellar ataxia 1

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chr6:16,299,112-16,761,491

External References & Databases

Ensembl (ENSG00000124788)

Transcript & Mutation Effects

hg38 • Region Span ~462.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spinocerebellar ataxia type 1MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0008119

Submitter: Ambry Genetics

spinocerebellar ataxia type 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008119

Submitter: Labcorp Genetics (formerly Invitae)

spinocerebellar ataxia type 1SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008119

Submitter: Orphanet

Clinical Genomic Database (CGD)

Spinocerebellar ataxia 1AD

Manifestation: Neurologic

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: 8275090; 8358429; 7951322; 8198139; 8037204; 8615077; 10424816; 11973625; 14967775; 16133185; 15747371; 18262566; 18685131; 20301363

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATXN1 variants in ClinVar

7 Conditions Cataloged

Inborn genetic diseasesTotal: 106

not specifiedTotal: 51

not providedTotal: 35

ATXN1-related disorderTotal: 22

Spinocerebellar ataxia type 1Total: 10

Tip-toe gaitTotal: 2

SchizophreniaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001128164.2. 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 clinvar	29 clinvar	2 clinvar	34
missense			103 clinvar	25 clinvar		128
nonsense			4 clinvar			4
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)						0
Total	0	0	111	54	2	167

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001128164.2	RefSeq	NP_001121636.1	2	MANE Select
ENST00000436367.6	Ensembl	ENSP00000416360.1	2	MANE Select
NM_000332.4	RefSeq	NP_000323.2	2	Standard
NM_001357857.2	RefSeq	NP_001344786.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of transcription by RNA polymerase II
RNA processing
brain development
learning
memory

Molecular Function

DNA binding
protein binding
protein C-terminus binding
poly(U) RNA binding
poly(G) binding

Cellular Component

nucleus
nucleoplasm
nucleolus
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000244769
Coding exons: 2
Length: 462380
Individuals with no LoFs: 125674
Homozygous LoFs: 24
Heterozygous LoFs: 28
Defined: 125726
p: 0.000207

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.25	434	514	0.845	0.0000353	5214
Missense (PolyPhen)		105	172.15	0.60994		1741
Synonymous	-1.98	290	250	1.16	0.0000211	1750
Loss of Function	4.03	3	24.6	0.122	0.00000117	259

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00066	0.00018	rare
Latino/Admixed American	0.00088	0.00035	rare
Ashkenazi Jewish	0.00041	0.00020	rare
East Asian	0.00068	0.00027	rare
Finnish	0.00029	0.00023	rare
European (Non-Finnish)	0.00029	0.00011	rare
South Asian	0.00086	0.00039	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Chromatin-binding factor that repress Notch signaling in the absence of Notch intracellular domain by acting as a CBF1 corepressor. Binds to the HEY promoter and might assist, along with NCOR2, RBPJ-mediated repression. Binds RNA in vitro. May be involved in RNA metabolism (PubMed:21475249). In concert with CIC and ATXN1L, involved in brain development (By similarity). {ECO:0000250|UniProtKB:P54254, ECO:0000269|PubMed:21475249}.;
Disease: DISEASE: Spinocerebellar ataxia 1 (SCA1) [MIM:164400]: 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 cerebellum degeneration with variable involvement of the brainstem and spinal cord. SCA1 belongs to the autosomal dominant cerebellar ataxias type I (ADCA I) which are characterized by cerebellar ataxia in combination with additional clinical features like optic atrophy, ophthalmoplegia, bulbar and extrapyramidal signs, peripheral neuropathy and dementia. SCA1 is caused by expansion of a CAG repeat in the coding region of ATXN1. Longer expansions result in earlier onset and more severe clinical manifestations of the disease. {ECO:0000269|PubMed:7647801, ECO:0000269|PubMed:7951322, ECO:0000269|PubMed:8634720}. Note=The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by expansion of the polyglutamine tract to about 40-83 repeats, causing accumulation in neurons and exerting toxicity. {ECO:0000269|PubMed:7647801, ECO:0000269|PubMed:8634720}.;

Recessive Scores

pRec: 0.429

Intolerance Scores

LoFtool: 0.0948
RVIS EVS: -0.52
RVIS percentile EVS: 20.94

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.934

Gene Damage Prediction

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