rs201030692

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001128164.2(ATXN1):c.621G>T(p.Gln207His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000363 in 1,409,294 control chromosomes in the GnomAD database, including 1 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. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 1 hom. )

Consequence

ATXN1
NM_001128164.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -2.06

Publications

20 publications found

Variant links:

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)

ATXN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032785237).

BP6

Variant 6-16327690-C-A is Benign according to our data. Variant chr6-16327690-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210502.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ATXN1	NM_001128164.2 link	c.621G>T	p.Gln207His	missense_variant	Exon 7 of 8	ENST00000436367.6	NP_001121636.1
ATXN1	NM_000332.4 link	c.621G>T	p.Gln207His	missense_variant	Exon 8 of 9		NP_000323.2
ATXN1	NM_001357857.2 link	c.*34G>T		3_prime_UTR_variant	Exon 8 of 9		NP_001344786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ATXN1	ENST00000436367.6 link	c.621G>T	p.Gln207His	missense_variant	Exon 7 of 8	1	NM_001128164.2	ENSP00000416360.1
ATXN1	ENST00000244769.8 link	c.621G>T	p.Gln207His	missense_variant	Exon 8 of 9	1		ENSP00000244769.3
ATXN1	ENST00000642969.1 link	c.*34G>T		downstream_gene_variant				ENSP00000493530.1

Frequencies

GnomAD3 genomes

AF:

0.000570

AC:

AN:

138632

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000907

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000222

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000201

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000210

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000534

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000642

AC:

106

AN:

165226

AF XY:

0.000546

show subpopulations

Gnomad AFR exome

AF:

0.00102

Gnomad AMR exome

AF:

0.000542

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000831

Gnomad FIN exome

AF:

0.000674

Gnomad NFE exome

AF:

0.000794

Gnomad OTH exome

AF:

0.000229

GnomAD4 exome

AF:

0.000340

AC:

432

AN:

1270584

Hom.:

Cov.:

AF XY:

0.000338

AC XY:

213

AN XY:

630484

show subpopulations

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

African (AFR)

AF:

0.00108

AC:

AN:

27662

American (AMR)

AF:

0.000569

AC:

AN:

33390

Ashkenazi Jewish (ASJ)

AF:

0.0000409

AC:

AN:

24432

East Asian (EAS)

AF:

0.00121

AC:

AN:

24006

South Asian (SAS)

AF:

0.000406

AC:

AN:

66528

European-Finnish (FIN)

AF:

0.000735

AC:

AN:

38112

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

4908

European-Non Finnish (NFE)

AF:

0.000266

AC:

266

AN:

999662

Other (OTH)

AF:

0.000501

AC:

AN:

51884

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.320

Heterozygous variant carriers

104

130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000570

AC:

AN:

138710

Hom.:

Cov.:

AF XY:

0.000518

AC XY:

AN XY:

67622

show subpopulations

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

African (AFR)

AF:

0.000905

AC:

AN:

38666

American (AMR)

AF:

0.000222

AC:

AN:

13532

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3296

East Asian (EAS)

AF:

0.000202

AC:

AN:

4956

South Asian (SAS)

AF:

0.00125

AC:

AN:

4012

European-Finnish (FIN)

AF:

0.000210

AC:

AN:

9540

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.000534

AC:

AN:

61766

Other (OTH)

AF:

0.00

AC:

AN:

1898

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.360

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0174

Hom.:

ExAC

AF:

0.00307

AC:

332

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 27, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spinocerebellar ataxia type 1

Benign:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

0.55

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.28

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0046

LIST_S2

Benign

0.24

.;T

MetaRNN

Benign

0.0033

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

PhyloP100

-2.1

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.27

N;N

REVEL

Benign

0.14

Sift

Benign

0.10

T;T

Sift4G

Uncertain

0.015

D;D

Polyphen

0.97

D;D

Vest4

0.12

MutPred

0.20

Loss of solvent accessibility (P = 0.4653);Loss of solvent accessibility (P = 0.4653);

MVP

0.60

MPC

0.39

ClinPred

0.016

GERP RS

-0.093

Varity_R

0.10

gMVP

0.44

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over