chr6-16745299-G-A

Variant names:

• chr6-16745299-G-A
• rs547491
• NM_001128164.2:c.-615+7934C>T

Variant summary

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

The NM_000332.4(ATXN1):​c.-615+7934C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.684 in 152,076 control chromosomes in the GnomAD database, including 36,625 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 0.68 (36625 hom., cov: 32)
• Consequence: ATXN1 NM_000332.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.33
• Publications: 1 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.915 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000332.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN1	NM_001128164.2	MANE Select	c.-615+7934C>T		intron	N/A	NP_001121636.1
	ATXN1	NM_000332.4		c.-615+7934C>T		intron	N/A	NP_000323.2
	ATXN1	NM_001357857.2		c.-644+7934C>T		intron	N/A	NP_001344786.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN1	ENST00000436367.6	TSL:1 MANE Select	c.-615+7934C>T		intron	N/A	ENSP00000416360.1
	ATXN1	ENST00000244769.8	TSL:1	c.-615+7934C>T		intron	N/A	ENSP00000244769.3
	ATXN1	ENST00000467008.5	TSL:1	n.295-5381C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.684 AC: 103922 AN: 151960 Hom.: 36590 Cov.: 32

Gnomad AFR AF: 0.834

Gnomad AMI AF: 0.596

Gnomad AMR AF: 0.688

Gnomad ASJ AF: 0.669

Gnomad EAS AF: 0.937

Gnomad SAS AF: 0.730

Gnomad FIN AF: 0.513

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.598

Gnomad OTH AF: 0.676

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

GnomAD4 genome AF: 0.684 AC: 104009 AN: 152076 Hom.: 36625 Cov.: 32 AF XY: 0.683 AC XY: 50791 AN XY: 74324

African (AFR) AF: 0.834 AC: 34595 AN: 41504

American (AMR) AF: 0.688 AC: 10509 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.669 AC: 2319 AN: 3464

East Asian (EAS) AF: 0.937 AC: 4856 AN: 5182

South Asian (SAS) AF: 0.730 AC: 3522 AN: 4826

European-Finnish (FIN) AF: 0.513 AC: 5407 AN: 10536

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.598 AC: 40623 AN: 67968

Other (OTH) AF: 0.679 AC: 1435 AN: 2112

Alfa AF: 0.636 Hom.: 104575

Bravo AF: 0.707

Asia WGS AF: 0.824 AC: 2863 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	6.7
DANN	Benign	0.62
PhyloP100		1.3
Mutation Taster		=99/1	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: rs547491; hg19: chr6-16745530;