rs179997

Variant names:

• chr6-16318402-T-A
• rs179997
• NM_001128164.2:c.1917+7992A>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.1917+7992A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 152,082 control chromosomes in the GnomAD database, including 7,439 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 0.28 (7439 hom., cov: 32)
• Consequence: ATXN1 NM_001128164.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.417
• Publications: 12 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN1	NM_001128164.2	c.1917+7992A>T		intron_variant	Intron 7 of 7	ENST00000436367.6	NP_001121636.1
ATXN1	NM_000332.4	c.1917+7992A>T		intron_variant	Intron 8 of 8		NP_000323.2
ATXN1	NM_001357857.2	c.*1330+7992A>T		intron_variant	Intron 8 of 8		NP_001344786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN1	ENST00000436367.6	c.1917+7992A>T		intron_variant	Intron 7 of 7	1	NM_001128164.2	ENSP00000416360.1
ATXN1	ENST00000244769.8	c.1917+7992A>T		intron_variant	Intron 8 of 8	1		ENSP00000244769.3

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42850 AN: 151966 Hom.: 7441 Cov.: 32

Gnomad AFR AF: 0.0832

Gnomad AMI AF: 0.464

Gnomad AMR AF: 0.356

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.326

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.296

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

GnomAD4 genome AF: 0.282 AC: 42858 AN: 152082 Hom.: 7439 Cov.: 32 AF XY: 0.280 AC XY: 20806 AN XY: 74338

African (AFR) AF: 0.0832 AC: 3456 AN: 41532

American (AMR) AF: 0.356 AC: 5442 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1039 AN: 3468

East Asian (EAS) AF: 0.132 AC: 685 AN: 5180

South Asian (SAS) AF: 0.239 AC: 1153 AN: 4818

European-Finnish (FIN) AF: 0.326 AC: 3442 AN: 10562

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.391 AC: 26531 AN: 67936

Other (OTH) AF: 0.292 AC: 617 AN: 2110

Alfa AF: 0.338 Hom.: 1195

Bravo AF: 0.277

Asia WGS AF: 0.157 AC: 549 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.87
DANN	Benign	0.79
PhyloP100		-0.42
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: rs179997; hg19: chr6-16318633;