6-16306520-G-A

Position:

chr6-16306520-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001128164.2(ATXN1):c.2257C>T(p.Pro753Ser) variant causes a missense change. The variant allele was found at a frequency of 0.187 in 1,614,034 control chromosomes in the GnomAD database, including 30,868 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.15 ( 2367 hom., cov: 32)

Exomes 𝑓: 0.19 ( 28501 hom. )

Consequence

ATXN1
NM_001128164.2 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 4.47

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0012945831).

BP6

Variant 6-16306520-G-A is Benign according to our data. Variant chr6-16306520-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128499.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-16306520-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ATXN1	NM_001128164.2 linkuse as main transcript	c.2257C>T	p.Pro753Ser	missense_variant	8/8	ENST00000436367.6
ATXN1	NM_000332.4 linkuse as main transcript	c.2257C>T	p.Pro753Ser	missense_variant	9/9
ATXN1	NM_001357857.2 linkuse as main transcript	c.*1670C>T		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN1	ENST00000436367.6 linkuse as main transcript	c.2257C>T	p.Pro753Ser	missense_variant	8/8	1	NM_001128164.2	P1	P54253-1
ATXN1	ENST00000244769.8 linkuse as main transcript	c.2257C>T	p.Pro753Ser	missense_variant	9/9	1		P1	P54253-1

Frequencies

GnomAD3 genomes

AF:

0.155

AC:

23559

AN:

152034

Hom.:

2367

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0412

Gnomad AMI

AF:

0.406

Gnomad AMR

AF:

0.242

Gnomad ASJ

AF:

0.249

Gnomad EAS

AF:

0.00597

Gnomad SAS

AF:

0.197

Gnomad FIN

AF:

0.198

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.197

Gnomad OTH

AF:

0.177

GnomAD3 exomes

AF:

0.195

AC:

48925

AN:

251454

Hom.:

5729

AF XY:

0.195

AC XY:

26550

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0332

Gnomad AMR exome

AF:

0.326

Gnomad ASJ exome

AF:

0.252

Gnomad EAS exome

AF:

0.00843

Gnomad SAS exome

AF:

0.197

Gnomad FIN exome

AF:

0.192

Gnomad NFE exome

AF:

0.202

Gnomad OTH exome

AF:

0.206

GnomAD4 exome

AF:

0.190

AC:

278317

AN:

1461882

Hom.:

28501

Cov.:

AF XY:

0.191

AC XY:

139000

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0311

Gnomad4 AMR exome

AF:

0.315

Gnomad4 ASJ exome

AF:

0.252

Gnomad4 EAS exome

AF:

0.00390

Gnomad4 SAS exome

AF:

0.193

Gnomad4 FIN exome

AF:

0.189

Gnomad4 NFE exome

AF:

0.196

Gnomad4 OTH exome

AF:

0.173

GnomAD4 genome

AF:

0.155

AC:

23564

AN:

152152

Hom.:

2367

Cov.:

AF XY:

0.158

AC XY:

11752

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0411

Gnomad4 AMR

AF:

0.243

Gnomad4 ASJ

AF:

0.249

Gnomad4 EAS

AF:

0.00579

Gnomad4 SAS

AF:

0.198

Gnomad4 FIN

AF:

0.198

Gnomad4 NFE

AF:

0.197

Gnomad4 OTH

AF:

0.175

Alfa

AF:

0.190

Hom.:

7287

Bravo

AF:

0.154

TwinsUK

AF:

0.195

AC:

723

ALSPAC

AF:

0.200

AC:

771

ESP6500AA

AF:

0.0413

AC:

182

ESP6500EA

AF:

0.197

AC:

1693

ExAC

AF:

0.189

AC:

22911

EpiCase

AF:

0.205

EpiControl

AF:

0.199

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.25

T;T

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.80

.;T

MetaRNN

Benign

0.0013

T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.4

L;L

MutationTaster

Benign

0.11

P;P;P

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.1

N;N

REVEL

Uncertain

0.32

Sift

Uncertain

0.015

D;D

Sift4G

Uncertain

0.015

D;D

Polyphen

0.29

B;B

Vest4

0.10

MPC

1.2

ClinPred

0.013

GERP RS

6.1

Varity_R

0.097

gMVP

0.19

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over