rs1476464

Variant names:

• chr6-16392057-A-C
• rs1476464
• NM_001128164.2:c.-160-63587T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001128164.2(ATXN1):​c.-160-63587T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 152,188 control chromosomes in the GnomAD database, including 2,033 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (2033 hom., cov: 32)
• Consequence: ATXN1 NM_001128164.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.315
• Publications: 3 publications found

Genes affected

ATXN1 (HGNC:10548): (ataxin 1) 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]

ATXN1 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 1

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN1	NM_001128164.2	c.-160-63587T>G		intron_variant	Intron 6 of 7	ENST00000436367.6	NP_001121636.1
ATXN1	NM_000332.4	c.-160-63587T>G		intron_variant	Intron 7 of 8		NP_000323.2
ATXN1	NM_001357857.2	c.-189-63587T>G		intron_variant	Intron 7 of 8		NP_001344786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN1	ENST00000436367.6	c.-160-63587T>G		intron_variant	Intron 6 of 7	1	NM_001128164.2	ENSP00000416360.1
ATXN1	ENST00000244769.8	c.-160-63587T>G		intron_variant	Intron 7 of 8	1		ENSP00000244769.3

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23268 AN: 152070 Hom.: 2031 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.0279

Gnomad SAS AF: 0.0408

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.142

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.153 AC: 23292 AN: 152188 Hom.: 2033 Cov.: 32 AF XY: 0.149 AC XY: 11082 AN XY: 74410

African (AFR) AF: 0.233 AC: 9680 AN: 41488

American (AMR) AF: 0.117 AC: 1795 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 432 AN: 3470

East Asian (EAS) AF: 0.0280 AC: 145 AN: 5186

South Asian (SAS) AF: 0.0410 AC: 198 AN: 4826

European-Finnish (FIN) AF: 0.111 AC: 1178 AN: 10610

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9422 AN: 68006

Other (OTH) AF: 0.140 AC: 296 AN: 2108

Alfa AF: 0.143 Hom.: 260

Bravo AF: 0.158

Asia WGS AF: 0.0540 AC: 186 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	2.4
DANN	Benign	0.82
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1476464; hg19: chr6-16392288;