NM_001128164.2:c.630G>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001128164.2(ATXN1):c.630G>T(p.Gln210His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 116,300 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ATXN1
NM_001128164.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.00

Publications

11 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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09375334).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN1	NM_001128164.2 link	c.630G>T	p.Gln210His	missense_variant	Exon 7 of 8	ENST00000436367.6	NP_001121636.1	P54253-1Q96FF1
ATXN1	NM_000332.4 link	c.630G>T	p.Gln210His	missense_variant	Exon 8 of 9		NP_000323.2	P54253-1Q96FF1
ATXN1	NM_001357857.2 link	c.*43G>T		3_prime_UTR_variant	Exon 8 of 9		NP_001344786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ATXN1	ENST00000436367.6 link	c.630G>T	p.Gln210His	missense_variant	Exon 7 of 8	1	NM_001128164.2	ENSP00000416360.1	P54253-1
ATXN1	ENST00000244769.8 link	c.630G>T	p.Gln210His	missense_variant	Exon 8 of 9	1		ENSP00000244769.3	P54253-1
ATXN1	ENST00000642969.1 link	c.*43G>T		downstream_gene_variant				ENSP00000493530.1	A0A2R8YCF3

Frequencies

GnomAD3 genomes

AF:

0.000129

AC:

AN:

116300

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000281

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000925

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000115

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000157

AC:

AN:

127286

AF XY:

0.0000139

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000336

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000388

AC:

AN:

1314922

Hom.:

Cov.:

AF XY:

0.0000396

AC XY:

AN XY:

656322

show subpopulations

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

African (AFR)

AF:

0.0000965

AC:

AN:

20736

American (AMR)

AF:

0.00

AC:

AN:

36428

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24992

East Asian (EAS)

AF:

0.000103

AC:

AN:

29224

South Asian (SAS)

AF:

0.0000267

AC:

AN:

74982

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4854

European-Non Finnish (NFE)

AF:

0.0000418

AC:

AN:

1028246

Other (OTH)

AF:

0.0000188

AC:

AN:

53064

⚠️ 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: 0.272

Heterozygous variant carriers

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:

0.000129

AC:

AN:

116300

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

56144

show subpopulations

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

African (AFR)

AF:

0.000281

AC:

AN:

24926

American (AMR)

AF:

0.0000925

AC:

AN:

10806

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3132

East Asian (EAS)

AF:

0.00

AC:

AN:

2542

South Asian (SAS)

AF:

0.00

AC:

AN:

3356

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8444

Middle Eastern (MID)

AF:

0.00

AC:

AN:

270

European-Non Finnish (NFE)

AF:

0.000115

AC:

AN:

60676

Other (OTH)

AF:

0.00

AC:

AN:

1568

⚠️ 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: 0.328

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:

0.00312

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 04, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Spinocerebellar ataxia type 1

Uncertain:1

Jan 12, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

CADD

Benign

7.1

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.18

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.19

.;T

M_CAP

Benign

0.059

MetaRNN

Benign

0.094

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

N;N

PhyloP100

0.0

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.39

N;N

REVEL

Benign

0.012

Sift

Benign

0.034

D;D

Sift4G

Uncertain

0.012

D;D

Vest4

0.17

MutPred

0.21

Loss of MoRF binding (P = 0.5121);Loss of MoRF binding (P = 0.5121);

MVP

0.68

MPC

0.39

ClinPred

0.11

Varity_R

0.12

gMVP

0.43

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