rs1997716

Positions:

• chr6-16600448-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001128164.2(ATXN1):​c.-488-14541A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.726 in 152,128 control chromosomes in the GnomAD database, including 40,228 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 0.73 (40228 hom., cov: 32)
• Consequence: ATXN1 NM_001128164.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.31

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN1	NM_001128164.2	c.-488-14541A>G		intron_variant		ENST00000436367.6	NP_001121636.1
ATXN1	NM_000332.4	c.-488-14541A>G		intron_variant			NP_000323.2
ATXN1	NM_001357857.2	c.-517-14541A>G		intron_variant			NP_001344786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN1	ENST00000436367.6	c.-488-14541A>G		intron_variant		1	NM_001128164.2	ENSP00000416360	P1

Frequencies

GnomAD3 genomes AF: 0.725 AC: 110275 AN: 152012 Hom.: 40186 Cov.: 32

Gnomad AFR AF: 0.690

Gnomad AMI AF: 0.780

Gnomad AMR AF: 0.836

Gnomad ASJ AF: 0.769

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.667

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.739

Gnomad OTH AF: 0.723

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

GnomAD4 genome AF: 0.726 AC: 110374 AN: 152128 Hom.: 40228 Cov.: 32 AF XY: 0.725 AC XY: 53925 AN XY: 74360

Gnomad4 AFR AF: 0.690

Gnomad4 AMR AF: 0.837

Gnomad4 ASJ AF: 0.769

Gnomad4 EAS AF: 0.552

Gnomad4 SAS AF: 0.765

Gnomad4 FIN AF: 0.667

Gnomad4 NFE AF: 0.739

Gnomad4 OTH AF: 0.722

Alfa AF: 0.744 Hom.: 41655

Bravo AF: 0.736

Asia WGS AF: 0.686 AC: 2389 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.91
DANN	Benign	0.56

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: rs1997716; hg19: chr6-16600679;