rs1801968

Positions:

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id is 5182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-129818622-C-G is described in Lovd as [Benign]. Variant chr9-129818622-C-G is described in Lovd as [Likely_benign].

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/exons	MANE	Protein	UniProt
TOR1A	NM_000113.3 linkuse as main transcript	c.646G>C	p.Asp216His	missense_variant	4/5	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.646G>C	p.Asp216His	missense_variant	4/5	1	NM_000113.3	ENSP00000345719	P1	O14656-1
TOR1A	ENST00000651202.1 linkuse as main transcript	c.742G>C	p.Asp248His	missense_variant	4/6			ENSP00000498222
TOR1A	ENST00000473604.2 linkuse as main transcript	n.756G>C		non_coding_transcript_exon_variant	4/4	5
TOR1A	ENST00000474192.1 linkuse as main transcript	n.63G>C		non_coding_transcript_exon_variant	2/3	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

GnomAD3 exomes

AF:

0.125

AC:

31486

AN:

251470

Hom.:

2219

AF XY:

0.129

AC XY:

17508

AN XY:

135910

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 SAS exome

AF:

0.145

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

Gnomad4 AFR exome

AF:

0.0214

Gnomad4 AMR exome

AF:

0.107

Gnomad4 ASJ exome

AF:

0.195

Gnomad4 EAS exome

AF:

0.0643

Gnomad4 SAS exome

AF:

0.150

Gnomad4 FIN exome

AF:

0.161

Gnomad4 NFE exome

AF:

0.140

Gnomad4 OTH exome

AF:

0.129

GnomAD4 genome

AF:

0.105

AC:

15937

AN:

152272

Hom.:

1065

Cov.:

AF XY:

0.107

AC XY:

7987

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0260

Gnomad4 AMR

AF:

0.105

Gnomad4 ASJ

AF:

0.198

Gnomad4 EAS

AF:

0.0732

Gnomad4 SAS

AF:

0.151

Gnomad4 FIN

AF:

0.165

Gnomad4 NFE

AF:

0.137

Gnomad4 OTH

AF:

0.110

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

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 31, 2024	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Early-onset generalized limb-onset dystonia

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 2018	This variant is associated with the following publications: (PMID: 31583275, 17503336, 26940431, 23405979, 18519876, 19380705, 23460578, 20669276, 16537570) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Dystonic disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Early-onset generalized limb-onset dystonia;C5436453:Arthrogryposis multiplex congenita 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 01, 2021

- -

DYSTONIA 1, TORSION, MODIFIER OF

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Sep 15, 2010

- -

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

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

MutationTaster

Benign

0.039

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

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

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