22-45738761-G-A

Position:

chr22-45738761-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The ENST00000252934.10(ATXN10):c.925G>A(p.Val309Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000494 in 1,613,878 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 1 hom. )

Consequence

ATXN10
ENST00000252934.10 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 3.38

Variant links:

Genes affected

ATXN10 (HGNC:10549): (ataxin 10) This gene encodes a protein that may function in neuron survival, neuron differentiation, and neuritogenesis. These roles may be carried out via activation of the mitogen-activated protein kinase cascade. Expansion of an ATTCT repeat from 9-32 copies to 800-4500 copies in an intronic region of this locus has been associated with spinocerebellar ataxia, type 10. Alternatively spliced transcript variants have been described.[provided by RefSeq, Jul 2016]

ATXN10 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07922596).

BP6

Variant 22-45738761-G-A is Benign according to our data. Variant chr22-45738761-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3132195.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 49 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ATXN10	NM_013236.4 linkuse as main transcript	c.925G>A	p.Val309Ile	missense_variant	8/12	ENST00000252934.10	NP_037368.1
ATXN10	NM_001167621.2 linkuse as main transcript	c.733G>A	p.Val245Ile	missense_variant	7/11		NP_001161093.1
ATXN10	XM_047441314.1 linkuse as main transcript	c.925G>A	p.Val309Ile	missense_variant	8/12		XP_047297270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN10	ENST00000252934.10 linkuse as main transcript	c.925G>A	p.Val309Ile	missense_variant	8/12	1	NM_013236.4	ENSP00000252934	P1	Q9UBB4-1

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000346

AC:

AN:

251294

Hom.:

AF XY:

0.000324

AC XY:

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000324

Gnomad NFE exome

AF:

0.000642

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000512

AC:

749

AN:

1461762

Hom.:

Cov.:

AF XY:

0.000507

AC XY:

369

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000187

Gnomad4 NFE exome

AF:

0.000645

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000322

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000447

Hom.:

Bravo

AF:

0.000268

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000404

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

ATXN10-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 26, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

.;T;.;.

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.022

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.85

D;D;T;D

M_CAP

Benign

0.0072

MetaRNN

Benign

0.079

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

.;L;.;.

MutationTaster

Benign

0.86

D;D

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.070

N;N;.;N

REVEL

Benign

0.086

Sift

Benign

0.27

T;T;.;T

Sift4G

Benign

0.56

T;T;.;T

Polyphen

0.53

.;P;.;.

Vest4

0.23

MVP

0.38

MPC

0.053

ClinPred

0.034

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.028

gMVP

0.13

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