6-16749336-A-G

Variant names:

• chr6-16749336-A-G
• rs607138
• NM_001128164.2:c.-615+3897T>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.-615+3897T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 152,128 control chromosomes in the GnomAD database, including 31,264 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 0.64 (31264 hom., cov: 32)
• Consequence: ATXN1 NM_001128164.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.14
• 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, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.807 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128164.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN1	NM_001128164.2	MANE Select	c.-615+3897T>C		intron	N/A	NP_001121636.1	P54253-1
	ATXN1	NM_000332.4		c.-615+3897T>C		intron	N/A	NP_000323.2	P54253-1
	ATXN1	NM_001357857.2		c.-644+3897T>C		intron	N/A	NP_001344786.1	A0A2R8YCF3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN1	ENST00000436367.6	TSL:1 MANE Select	c.-615+3897T>C		intron	N/A	ENSP00000416360.1	P54253-1
	ATXN1	ENST00000244769.8	TSL:1	c.-615+3897T>C		intron	N/A	ENSP00000244769.3	P54253-1
	ATXN1	ENST00000467008.5	TSL:1	n.294+3897T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.635 AC: 96584 AN: 152010 Hom.: 31232 Cov.: 32

Gnomad AFR AF: 0.740

Gnomad AMI AF: 0.531

Gnomad AMR AF: 0.660

Gnomad ASJ AF: 0.632

Gnomad EAS AF: 0.828

Gnomad SAS AF: 0.668

Gnomad FIN AF: 0.509

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.571

Gnomad OTH AF: 0.633

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

GnomAD4 genome AF: 0.635 AC: 96660 AN: 152128 Hom.: 31264 Cov.: 32 AF XY: 0.635 AC XY: 47238 AN XY: 74352

African (AFR) AF: 0.739 AC: 30690 AN: 41508

American (AMR) AF: 0.660 AC: 10085 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.632 AC: 2195 AN: 3472

East Asian (EAS) AF: 0.828 AC: 4284 AN: 5176

South Asian (SAS) AF: 0.669 AC: 3224 AN: 4822

European-Finnish (FIN) AF: 0.509 AC: 5376 AN: 10564

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.571 AC: 38786 AN: 67982

Other (OTH) AF: 0.635 AC: 1343 AN: 2114

Alfa AF: 0.592 Hom.: 13527

Bravo AF: 0.655

Asia WGS AF: 0.714 AC: 2485 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.099
DANN	Benign	0.42
PhyloP100		-2.1
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: rs607138; hg19: chr6-16749567; COSMIC: COSV55222561; COSMIC: COSV55222561;