6-16387572-A-G

Variant names:

• chr6-16387572-A-G
• rs9464886
• NM_001128164.2:c.-160-59102T>C

Variant summary

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

The NM_001128164.2(ATXN1):​c.-160-59102T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 152,158 control chromosomes in the GnomAD database, including 1,986 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 0.16 (1986 hom., cov: 32)
• Consequence: ATXN1 NM_001128164.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0950
• Publications: 4 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN1	NM_001128164.2	c.-160-59102T>C		intron_variant	Intron 6 of 7	ENST00000436367.6	NP_001121636.1
ATXN1	NM_000332.4	c.-160-59102T>C		intron_variant	Intron 7 of 8		NP_000323.2
ATXN1	NM_001357857.2	c.-189-59102T>C		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.-160-59102T>C		intron_variant	Intron 6 of 7	1	NM_001128164.2	ENSP00000416360.1
ATXN1	ENST00000244769.8	c.-160-59102T>C		intron_variant	Intron 7 of 8	1		ENSP00000244769.3

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23826 AN: 152040 Hom.: 1983 Cov.: 32

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.0452

Gnomad SAS AF: 0.0640

Gnomad FIN AF: 0.0980

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.169

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

GnomAD4 genome AF: 0.157 AC: 23852 AN: 152158 Hom.: 1986 Cov.: 32 AF XY: 0.152 AC XY: 11310 AN XY: 74380

African (AFR) AF: 0.192 AC: 7978 AN: 41502

American (AMR) AF: 0.144 AC: 2201 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 717 AN: 3472

East Asian (EAS) AF: 0.0451 AC: 234 AN: 5186

South Asian (SAS) AF: 0.0641 AC: 309 AN: 4822

European-Finnish (FIN) AF: 0.0980 AC: 1038 AN: 10596

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10816 AN: 67980

Other (OTH) AF: 0.170 AC: 359 AN: 2112

Alfa AF: 0.159 Hom.: 8771

Bravo AF: 0.162

Asia WGS AF: 0.0710 AC: 246 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	7.3
DANN	Benign	0.70
PhyloP100		0.095
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: rs9464886; hg19: chr6-16387803;