rs179972

Variant names:

• chr6-16362461-C-T
• rs179972
• NM_001128164.2:c.-160-33991G>A

Variant summary

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

The NM_001128164.2(ATXN1):​c.-160-33991G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 152,016 control chromosomes in the GnomAD database, including 8,987 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 0.31 (8987 hom., cov: 31)
• Consequence: ATXN1 NM_001128164.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.556
• Publications: 5 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN1	NM_001128164.2	c.-160-33991G>A		intron_variant	Intron 6 of 7	ENST00000436367.6	NP_001121636.1
ATXN1	NM_000332.4	c.-160-33991G>A		intron_variant	Intron 7 of 8		NP_000323.2
ATXN1	NM_001357857.2	c.-189-33991G>A		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.-160-33991G>A		intron_variant	Intron 6 of 7	1	NM_001128164.2	ENSP00000416360.1
ATXN1	ENST00000244769.8	c.-160-33991G>A		intron_variant	Intron 7 of 8	1		ENSP00000244769.3

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46689 AN: 151896 Hom.: 8989 Cov.: 31

Gnomad AFR AF: 0.0841

Gnomad AMI AF: 0.496

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.0932

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.337

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

GnomAD4 genome AF: 0.307 AC: 46696 AN: 152016 Hom.: 8987 Cov.: 31 AF XY: 0.305 AC XY: 22656 AN XY: 74312

African (AFR) AF: 0.0841 AC: 3490 AN: 41514

American (AMR) AF: 0.377 AC: 5748 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 1278 AN: 3466

East Asian (EAS) AF: 0.0932 AC: 482 AN: 5172

South Asian (SAS) AF: 0.278 AC: 1334 AN: 4800

European-Finnish (FIN) AF: 0.353 AC: 3724 AN: 10554

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.433 AC: 29392 AN: 67952

Other (OTH) AF: 0.334 AC: 702 AN: 2104

Alfa AF: 0.390 Hom.: 4217

Bravo AF: 0.302

Asia WGS AF: 0.163 AC: 568 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.76
DANN	Benign	0.78
PhyloP100		-0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.4
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: rs179972; hg19: chr6-16362692;