rs2296793

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000113.3(TOR1A):c.246C>T(p.Ala82Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,613,904 control chromosomes in the GnomAD database, including 45,524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4075 hom., cov: 32)

Exomes 𝑓: 0.24 ( 41449 hom. )

Consequence

TOR1A
NM_000113.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -3.50

Publications

43 publications found

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 Gene-Disease associations (from GenCC):

early-onset generalized limb-onset dystonia
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Illumina, Orphanet
arthrogryposis multiplex congenita 5
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

TOR1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 9-129822779-G-A is Benign according to our data. Variant chr9-129822779-G-A is described in ClinVar as Benign. ClinVar VariationId is 255134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.5 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOR1A	NM_000113.3 link	c.246C>T	p.Ala82Ala	synonymous_variant	Exon 2 of 5	ENST00000351698.5	NP_000104.1	O14656-1B3KPA1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TOR1A	ENST00000351698.5 link	c.246C>T	p.Ala82Ala	synonymous_variant	Exon 2 of 5	1	NM_000113.3	ENSP00000345719.4	O14656-1
TOR1A	ENST00000473084.1 link	n.265C>T		non_coding_transcript_exon_variant	Exon 2 of 2	1
TOR1A	ENST00000651202.1 link	c.342C>T	p.Ala114Ala	synonymous_variant	Exon 2 of 6			ENSP00000498222.1	A0A494BZT7
TOR1A	ENST00000473604.2 link	n.356C>T		non_coding_transcript_exon_variant	Exon 2 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.229

AC:

34865

AN:

151944

Hom.:

4076

Cov.:

show subpopulations

Gnomad AFR

AF:

0.219

Gnomad AMI

AF:

0.171

Gnomad AMR

AF:

0.212

Gnomad ASJ

AF:

0.217

Gnomad EAS

AF:

0.221

Gnomad SAS

AF:

0.207

Gnomad FIN

AF:

0.252

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.240

Gnomad OTH

AF:

0.237

GnomAD2 exomes

AF:

0.224

AC:

56225

AN:

251480

AF XY:

0.226

show subpopulations

Gnomad AFR exome

AF:

0.224

Gnomad AMR exome

AF:

0.176

Gnomad ASJ exome

AF:

0.226

Gnomad EAS exome

AF:

0.200

Gnomad FIN exome

AF:

0.239

Gnomad NFE exome

AF:

0.240

Gnomad OTH exome

AF:

0.242

GnomAD4 exome

AF:

0.237

AC:

346107

AN:

1461840

Hom.:

41449

Cov.:

AF XY:

0.236

AC XY:

171551

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.216

AC:

7236

AN:

33478

American (AMR)

AF:

0.180

AC:

8042

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.225

AC:

5887

AN:

26136

East Asian (EAS)

AF:

0.256

AC:

10156

AN:

39700

South Asian (SAS)

AF:

0.208

AC:

17967

AN:

86258

European-Finnish (FIN)

AF:

0.238

AC:

12707

AN:

53418

Middle Eastern (MID)

AF:

0.201

AC:

1157

AN:

5768

European-Non Finnish (NFE)

AF:

0.242

AC:

268826

AN:

1111962

Other (OTH)

AF:

0.234

AC:

14129

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

17617

35233

52850

70466

88083

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9154

18308

27462

36616

45770

<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:

0.229

AC:

34877

AN:

152064

Hom.:

4075

Cov.:

AF XY:

0.229

AC XY:

17033

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.219

AC:

9066

AN:

41452

American (AMR)

AF:

0.212

AC:

3234

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.217

AC:

751

AN:

3468

East Asian (EAS)

AF:

0.221

AC:

1145

AN:

5172

South Asian (SAS)

AF:

0.207

AC:

997

AN:

4820

European-Finnish (FIN)

AF:

0.252

AC:

2657

AN:

10560

Middle Eastern (MID)

AF:

0.235

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.240

AC:

16295

AN:

67984

Other (OTH)

AF:

0.240

AC:

507

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1358

2716

4074

5432

6790

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

362

724

1086

1448

1810

<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:

0.237

Hom.:

15143

Bravo

AF:

0.223

Asia WGS

AF:

0.238

AC:

824

AN:

3478

EpiCase

AF:

0.239

EpiControl

AF:

0.246

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 40% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 37. Only high quality variants are reported. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 17, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dystonic disorder

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Early-onset generalized limb-onset dystonia

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

6.2

(source)

DANN

Benign

0.72

PhyloP100

-3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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