rs12527937

Variant names:

• chr6-16544354-C-T
• rs12527937
• NM_001128164.2:c.-360-21666G>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.-360-21666G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 152,148 control chromosomes in the GnomAD database, including 1,380 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 0.13 (1380 hom., cov: 32)
• Consequence: ATXN1 NM_001128164.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.796
• 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN1	NM_001128164.2	c.-360-21666G>A		intron_variant	Intron 4 of 7	ENST00000436367.6	NP_001121636.1
ATXN1	NM_000332.4	c.-360-21666G>A		intron_variant	Intron 5 of 8		NP_000323.2
ATXN1	NM_001357857.2	c.-389-21666G>A		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.-360-21666G>A		intron_variant	Intron 4 of 7	1	NM_001128164.2	ENSP00000416360.1

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19522 AN: 152032 Hom.: 1374 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.392

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.0152

Gnomad SAS AF: 0.0723

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.122

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

GnomAD4 genome AF: 0.128 AC: 19543 AN: 152148 Hom.: 1380 Cov.: 32 AF XY: 0.129 AC XY: 9592 AN XY: 74368

African (AFR) AF: 0.147 AC: 6083 AN: 41504

American (AMR) AF: 0.146 AC: 2226 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 374 AN: 3470

East Asian (EAS) AF: 0.0154 AC: 80 AN: 5182

South Asian (SAS) AF: 0.0713 AC: 344 AN: 4822

European-Finnish (FIN) AF: 0.157 AC: 1655 AN: 10568

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.120 AC: 8140 AN: 68004

Other (OTH) AF: 0.121 AC: 256 AN: 2108

Alfa AF: 0.123 Hom.: 905

Bravo AF: 0.130

Asia WGS AF: 0.0540 AC: 186 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.1
DANN	Benign	0.66
PhyloP100		-0.80
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: rs12527937; hg19: chr6-16544585;