rs759132871

Variant names:

• chr6-16327675-CTGA-C
• rs759132871
• NM_001128164.2:c.633_635delTCA

Your query was ambiguous. Multiple possible variants found:

• chr6-16327675-CTGA-C
• chr6-16327675-CTGA-CTGATGA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_001128164.2(ATXN1):​c.633_635delTCA​(p.His211del) variant causes a disruptive 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. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.00
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001128164.2

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.633_635delTCA	p.His211del	disruptive_inframe_deletion	Exon 7 of 8	NP_001121636.1	P54253-1
	ATXN1	NM_000332.4		c.633_635delTCA	p.His211del	disruptive_inframe_deletion	Exon 8 of 9	NP_000323.2	P54253-1
	ATXN1	NM_001357857.2		c.*46_*48delTCA		3_prime_UTR	Exon 8 of 9	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.633_635delTCA	p.His211del	disruptive_inframe_deletion	Exon 7 of 8	ENSP00000416360.1	P54253-1
	ATXN1	ENST00000244769.8	TSL:1	c.633_635delTCA	p.His211del	disruptive_inframe_deletion	Exon 8 of 9	ENSP00000244769.3	P54253-1
	ATXN1	ENST00000642969.1		c.*46_*48delTCA		downstream_gene	N/A	ENSP00000493530.1	A0A2R8YCF3

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

GnomAD2 exomes AF: 0.00698 AC: 996 AN: 142684 AF XY: 0.00647

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0201 AC: 519 AN: 25870

American (AMR) AF: 0.00720 AC: 276 AN: 38318

Ashkenazi Jewish (ASJ) AF: 0.00287 AC: 72 AN: 25086

East Asian (EAS) AF: 0.0284 AC: 787 AN: 27696

South Asian (SAS) AF: 0.00730 AC: 569 AN: 77912

European-Finnish (FIN) AF: 0.00933 AC: 395 AN: 42346

Middle Eastern (MID) AF: 0.00274 AC: 14 AN: 5116

European-Non Finnish (NFE) AF: 0.00401 AC: 4310 AN: 1073902

Other (OTH) AF: 0.00866 AC: 485 AN: 55986

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0367 AC: 918 AN: 24980

American (AMR) AF: 0.0125 AC: 148 AN: 11828

Ashkenazi Jewish (ASJ) AF: 0.00604 AC: 19 AN: 3146

East Asian (EAS) AF: 0.0338 AC: 78 AN: 2310

South Asian (SAS) AF: 0.0106 AC: 37 AN: 3492

European-Finnish (FIN) AF: 0.0137 AC: 127 AN: 9258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 260

European-Non Finnish (NFE) AF: 0.0146 AC: 892 AN: 61272

Other (OTH) AF: 0.0125 AC: 21 AN: 1682

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=92/8	polymorphism

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: rs759132871; hg19: chr6-16327906; COSMIC: COSV55210391; COSMIC: COSV55210391;