chr9-129818622-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000113.3(TOR1A):c.646G>C(p.Asp216His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,614,148 control chromosomes in the GnomAD database, including 15,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 1065 hom., cov: 32)

Exomes 𝑓: 0.14 ( 14201 hom. )

Consequence

TOR1A
NM_000113.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:2

Conservation

PhyloP100: 1.30

Publications

81 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018074214).

BP6

Variant 9-129818622-C-G is Benign according to our data. Variant chr9-129818622-C-G is described in ClinVar as Benign. ClinVar VariationId is 5182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOR1A	NM_000113.3 link	c.646G>C	p.Asp216His	missense_variant	Exon 4 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.646G>C	p.Asp216His	missense_variant	Exon 4 of 5	1	NM_000113.3	ENSP00000345719.4	O14656-1
TOR1A	ENST00000651202.1 link	c.742G>C	p.Asp248His	missense_variant	Exon 4 of 6			ENSP00000498222.1	A0A494BZT7
TOR1A	ENST00000473604.2 link	n.756G>C		non_coding_transcript_exon_variant	Exon 4 of 4	5
TOR1A	ENST00000474192.1 link	n.63G>C		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

15936

AN:

152154

Hom.:

1062

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0261

Gnomad AMI

AF:

0.126

Gnomad AMR

AF:

0.105

Gnomad ASJ

AF:

0.198

Gnomad EAS

AF:

0.0732

Gnomad SAS

AF:

0.150

Gnomad FIN

AF:

0.165

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.137

Gnomad OTH

AF:

0.110

GnomAD2 exomes

AF:

0.125

AC:

31486

AN:

251470

AF XY:

0.129

show subpopulations

Gnomad AFR exome

AF:

0.0217

Gnomad AMR exome

AF:

0.104

Gnomad ASJ exome

AF:

0.195

Gnomad EAS exome

AF:

0.0827

Gnomad FIN exome

AF:

0.162

Gnomad NFE exome

AF:

0.135

Gnomad OTH exome

AF:

0.124

GnomAD4 exome

AF:

0.136

AC:

198663

AN:

1461876

Hom.:

14201

Cov.:

AF XY:

0.136

AC XY:

99191

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0214

AC:

718

AN:

33480

American (AMR)

AF:

0.107

AC:

4783

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.195

AC:

5090

AN:

26136

East Asian (EAS)

AF:

0.0643

AC:

2553

AN:

39700

South Asian (SAS)

AF:

0.150

AC:

12914

AN:

86258

European-Finnish (FIN)

AF:

0.161

AC:

8576

AN:

53402

Middle Eastern (MID)

AF:

0.127

AC:

732

AN:

5768

European-Non Finnish (NFE)

AF:

0.140

AC:

155509

AN:

1112012

Other (OTH)

AF:

0.129

AC:

7788

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

12131

24262

36394

48525

60656

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5594

11188

16782

22376

27970

<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:

0.105

AC:

15937

AN:

152272

Hom.:

1065

Cov.:

AF XY:

0.107

AC XY:

7987

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0260

AC:

1080

AN:

41576

American (AMR)

AF:

0.105

AC:

1599

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.198

AC:

686

AN:

3468

East Asian (EAS)

AF:

0.0732

AC:

379

AN:

5178

South Asian (SAS)

AF:

0.151

AC:

727

AN:

4830

European-Finnish (FIN)

AF:

0.165

AC:

1746

AN:

10594

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.137

AC:

9343

AN:

68010

Other (OTH)

AF:

0.110

AC:

233

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

738

1476

2213

2951

3689

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

200

400

600

800

1000

<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:

0.135

Hom.:

1127

Bravo

AF:

0.0969

TwinsUK

AF:

0.141

AC:

521

ALSPAC

AF:

0.140

AC:

541

ESP6500AA

AF:

0.0275

AC:

121

ESP6500EA

AF:

0.140

AC:

1203

ExAC

AF:

0.123

AC:

14903

Asia WGS

AF:

0.0950

AC:

329

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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 25% 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: 23. Only high quality variants are reported. -

May 21, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Early-onset generalized limb-onset dystonia

Benign:2Other:1

Mar 06, 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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

not provided

Benign:2

Aug 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31583275, 17503336, 26940431, 23405979, 18519876, 19380705, 23460578, 20669276, 16537570) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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;C5436453:Arthrogryposis multiplex congenita 5

Benign:1

Dec 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DYSTONIA 1, TORSION, MODIFIER OF

Other:1

Sep 15, 2010

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PhyloP100

1.3

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.6

REVEL

Benign

0.098

Sift

Uncertain

0.029

Sift4G

Uncertain

0.015

Polyphen

0.90

Vest4

0.12

MPC

1.0

ClinPred

0.036

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.082

gMVP

0.66

Mutation Taster

=84/16

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