rs28555263

chr6-16327687-C-Achr6-16327687-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001128164.2(ATXN1):c.624G>T(p.Gln208His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00466 in 122,690 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (27 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN1 NM_001128164.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.105

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002439618).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00466 (572/122690) while in subpopulation EAS AF= 0.0532 (118/2216). AF 95% confidence interval is 0.0455. There are 27 homozygotes in gnomad4. There are 289 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 570 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN1	NM_001128164.2	c.624G>T	p.Gln208His	missense_variant	7/8	ENST00000436367.6
ATXN1	NM_000332.4	c.624G>T	p.Gln208His	missense_variant	8/9
ATXN1	NM_001357857.2	c.*37G>T		3_prime_UTR_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN1	ENST00000436367.6	c.624G>T	p.Gln208His	missense_variant	7/8	1	NM_001128164.2	P1
ATXN1	ENST00000244769.8	c.624G>T	p.Gln208His	missense_variant	8/9	1		P1
ATXN1	ENST00000642969.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00465 AC: 570 AN: 122584 Hom.: 26 Cov.: 31

Gnomad AFR AF: 0.00406

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0532

Gnomad SAS AF: 0.0269

Gnomad FIN AF: 0.00115

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.00418

GnomAD3 exomes AF: 0.00447 AC: 601 AN: 134310 Hom.: 1 AF XY: 0.00402 AC XY: 302 AN XY: 75090

Gnomad AFR exome AF: 0.00175

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0201

Gnomad SAS exome AF: 0.00802

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.000680

Gnomad OTH exome AF: 0.00446

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00238 AC: 2629 AN: 1105690 Hom.: 5 Cov.: 33 AF XY: 0.00277 AC XY: 1523 AN XY: 549630

Gnomad4 AFR exome AF: 0.00195

Gnomad4 AMR exome AF: 0.0105

Gnomad4 ASJ exome AF: 0.0000914

Gnomad4 EAS exome AF: 0.0413

Gnomad4 SAS exome AF: 0.0163

Gnomad4 FIN exome AF: 0.00164

Gnomad4 NFE exome AF: 0.000678

Gnomad4 OTH exome AF: 0.00291

GnomAD4 genome AF: 0.00466 AC: 572 AN: 122690 Hom.: 27 Cov.: 31 AF XY: 0.00487 AC XY: 289 AN XY: 59306

Gnomad4 AFR AF: 0.00414

Gnomad4 AMR AF: 0.0123

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0532

Gnomad4 SAS AF: 0.0266

Gnomad4 FIN AF: 0.00115

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.00413

Alfa AF: 0.000426 Hom.: 0

ExAC AF: 0.000948 AC: 89

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

Jun 10, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	7.2
Dann	Benign	0.85
DEOGEN2	Benign	0.31	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.041	N
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.040	N;N
REVEL	Benign	0.033
Sift	Benign	1.0	T;T
Sift4G	Uncertain	0.010	D;D
Polyphen		0.68	P;P
Vest4		0.16
MutPred		0.28		Loss of solvent accessibility (P = 0.0635);Loss of solvent accessibility (P = 0.0635);
MVP		0.68
MPC		0.39
ClinPred		0.011	T
GERP RS		0.046
Varity_R		0.088
gMVP		0.44

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: rs28555263; hg19: chr6-16327918; COSMIC: COSV55208747; COSMIC: COSV55208747;