rs721010

Variant names:

• chr6-16572489-G-A
• rs721010
• NM_001128164.2:c.-361+13291C>T

Variant summary

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

The NM_001128164.2(ATXN1):​c.-361+13291C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 151,974 control chromosomes in the GnomAD database, including 18,903 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 0.47 (18903 hom., cov: 32)
• Consequence: ATXN1 NM_001128164.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0450
• 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.713 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN1	NM_001128164.2	c.-361+13291C>T		intron_variant	Intron 4 of 7	ENST00000436367.6	NP_001121636.1
ATXN1	NM_000332.4	c.-361+13291C>T		intron_variant	Intron 5 of 8		NP_000323.2
ATXN1	NM_001357857.2	c.-390+13291C>T		intron_variant	Intron 5 of 8		NP_001344786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN1	ENST00000436367.6	c.-361+13291C>T		intron_variant	Intron 4 of 7	1	NM_001128164.2	ENSP00000416360.1

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70808 AN: 151856 Hom.: 18879 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.714

Gnomad AMR AF: 0.592

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.733

Gnomad SAS AF: 0.687

Gnomad FIN AF: 0.577

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.540

Gnomad OTH AF: 0.480

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

GnomAD4 genome AF: 0.466 AC: 70851 AN: 151974 Hom.: 18903 Cov.: 32 AF XY: 0.474 AC XY: 35150 AN XY: 74232

African (AFR) AF: 0.194 AC: 8054 AN: 41468

American (AMR) AF: 0.593 AC: 9055 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 2044 AN: 3472

East Asian (EAS) AF: 0.733 AC: 3786 AN: 5166

South Asian (SAS) AF: 0.689 AC: 3316 AN: 4816

European-Finnish (FIN) AF: 0.577 AC: 6063 AN: 10502

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.540 AC: 36701 AN: 67960

Other (OTH) AF: 0.488 AC: 1029 AN: 2110

Alfa AF: 0.531 Hom.: 37114

Bravo AF: 0.457

Asia WGS AF: 0.682 AC: 2370 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.7
DANN	Benign	0.61
PhyloP100		-0.045
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: rs721010; hg19: chr6-16572720;