rs759132871

chr6-16327675-CTGA-Cchr6-16327675-CTGA-CTGATGA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001128164.2(ATXN1):c.633_635del(p.His211del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00648 in 1,491,270 control chromosomes in the GnomAD database, including 36 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.019 (30 hom., cov: 26)
  • Exomes 𝑓: 0.0054 (6 hom.)
• Consequence: ATXN1 NM_001128164.2 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0188 (2240/119038) while in subpopulation AFR AF= 0.0367 (918/24980). AF 95% confidence interval is 0.0348. There are 30 homozygotes in gnomad4. There are 1050 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 2230 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN1	NM_001128164.2	c.633_635del	p.His211del	inframe_deletion	7/8	ENST00000436367.6
ATXN1	NM_000332.4	c.633_635del	p.His211del	inframe_deletion	8/9
ATXN1	NM_001357857.2	c.*46_*48del		3_prime_UTR_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN1	ENST00000436367.6	c.633_635del	p.His211del	inframe_deletion	7/8	1	NM_001128164.2	P1
ATXN1	ENST00000244769.8	c.633_635del	p.His211del	inframe_deletion	8/9	1		P1
ATXN1	ENST00000642969.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2230 AN: 118948 Hom.: 29 Cov.: 26

Gnomad AFR AF: 0.0365

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.00604

Gnomad EAS AF: 0.0333

Gnomad SAS AF: 0.0103

Gnomad FIN AF: 0.0137

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.0126

GnomAD3 exomes AF: 0.00698 AC: 996 AN: 142684 Hom.: 1 AF XY: 0.00647 AC XY: 514 AN XY: 79412

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.00724

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.0207

Gnomad SAS exome AF: 0.00590

Gnomad FIN exome AF: 0.00380

Gnomad NFE exome AF: 0.00554

Gnomad OTH exome AF: 0.00766

GnomAD4 exome AF: 0.00541 AC: 7427 AN: 1372232 Hom.: 6 AF XY: 0.00556 AC XY: 3791 AN XY: 681406

Gnomad4 AFR exome AF: 0.0201

Gnomad4 AMR exome AF: 0.00720

Gnomad4 ASJ exome AF: 0.00287

Gnomad4 EAS exome AF: 0.0284

Gnomad4 SAS exome AF: 0.00730

Gnomad4 FIN exome AF: 0.00933

Gnomad4 NFE exome AF: 0.00401

Gnomad4 OTH exome AF: 0.00866

GnomAD4 genome AF: 0.0188 AC: 2240 AN: 119038 Hom.: 30 Cov.: 26 AF XY: 0.0181 AC XY: 1050 AN XY: 57866

Gnomad4 AFR AF: 0.0367

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.00604

Gnomad4 EAS AF: 0.0338

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.0137

Gnomad4 NFE AF: 0.0146

Gnomad4 OTH AF: 0.0125

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 15, 2014

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs759132871; hg19: chr6-16327906;