rs200493208

Positions:

chr9-129824060-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000113.3(TOR1A):c.26G>C(p.Gly9Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,596,450 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 8 hom., cov: 30)

Exomes 𝑓: 0.0014 ( 33 hom. )

Consequence

TOR1A
NM_000113.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0160

Variant links:

Genes affected

TOR1A (HGNC:3098): (torsin family 1 member A) The protein encoded by this gene is a member of the AAA family of adenosine triphosphatases (ATPases), is related to the Clp protease/heat shock family and is expressed prominently in the substantia nigra pars compacta. Mutations in this gene result in the autosomal dominant disorder, torsion dystonia 1. [provided by RefSeq, Jul 2008]

TOR1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006000489).

BP6

Variant 9-129824060-C-G is Benign according to our data. Variant chr9-129824060-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 365234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOR1A	NM_000113.3 linkuse as main transcript	c.26G>C	p.Gly9Ala	missense_variant	1/5	ENST00000351698.5	NP_000104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOR1A	ENST00000351698.5 linkuse as main transcript	c.26G>C	p.Gly9Ala	missense_variant	1/5	1	NM_000113.3	ENSP00000345719	P1	O14656-1
TOR1A	ENST00000473084.1 linkuse as main transcript	n.45G>C		non_coding_transcript_exon_variant	1/2	1
TOR1A	ENST00000651202.1 linkuse as main transcript	c.122G>C	p.Gly41Ala	missense_variant	1/6			ENSP00000498222

Frequencies

GnomAD3 genomes

AF:

0.00251

AC:

382

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000975

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0293

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00314

AC:

652

AN:

207596

Hom.:

AF XY:

0.00301

AC XY:

346

AN XY:

114816

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000110

Gnomad EAS exome

AF:

0.000738

Gnomad SAS exome

AF:

0.00107

Gnomad FIN exome

AF:

0.0319

Gnomad NFE exome

AF:

0.000983

Gnomad OTH exome

AF:

0.00454

GnomAD4 exome

AF:

0.00138

AC:

2000

AN:

1444208

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

979

AN XY:

717340

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000388

Gnomad4 EAS exome

AF:

0.000944

Gnomad4 SAS exome

AF:

0.00122

Gnomad4 FIN exome

AF:

0.0297

Gnomad4 NFE exome

AF:

0.000279

Gnomad4 OTH exome

AF:

0.00199

GnomAD4 genome

AF:

0.00251

AC:

382

AN:

152242

Hom.:

Cov.:

AF XY:

0.00386

AC XY:

287

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000977

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.0293

Gnomad4 NFE

AF:

0.000794

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00141

Hom.:

Bravo

AF:

0.000253

ExAC

AF:

0.00256

AC:

299

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

TOR1A: BS2 -

Dystonic disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

- -

Early-onset generalized limb-onset dystonia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.078

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.0043

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0060

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

MutationTaster

Benign

0.87

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.070

REVEL

Benign

0.087

Sift

Benign

1.0

Sift4G

Benign

0.67

Polyphen

0.0

Vest4

0.16

MVP

0.56

MPC

0.38

ClinPred

0.025

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.046

gMVP

0.80

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