rs2296793

Positions:

chr9-129822779-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000113.3(TOR1A):c.246C>T(p.Ala82=) 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

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 -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 id is 255134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-129822779-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
TOR1A	NM_000113.3 linkuse as main transcript	c.246C>T	p.Ala82=	synonymous_variant	2/5	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.246C>T	p.Ala82=	synonymous_variant	2/5	1	NM_000113.3	ENSP00000345719	P1	O14656-1
TOR1A	ENST00000473084.1 linkuse as main transcript	n.265C>T		non_coding_transcript_exon_variant	2/2	1
TOR1A	ENST00000651202.1 linkuse as main transcript	c.342C>T	p.Ala114=	synonymous_variant	2/6			ENSP00000498222
TOR1A	ENST00000473604.2 linkuse as main transcript	n.356C>T		non_coding_transcript_exon_variant	2/4	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

GnomAD3 exomes

AF:

0.224

AC:

56225

AN:

251480

Hom.:

6381

AF XY:

0.226

AC XY:

30775

AN XY:

135916

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 SAS exome

AF:

0.214

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

Gnomad4 AFR exome

AF:

0.216

Gnomad4 AMR exome

AF:

0.180

Gnomad4 ASJ exome

AF:

0.225

Gnomad4 EAS exome

AF:

0.256

Gnomad4 SAS exome

AF:

0.208

Gnomad4 FIN exome

AF:

0.238

Gnomad4 NFE exome

AF:

0.242

Gnomad4 OTH exome

AF:

0.234

GnomAD4 genome

AF:

0.229

AC:

34877

AN:

152064

Hom.:

4075

Cov.:

AF XY:

0.229

AC XY:

17033

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.219

Gnomad4 AMR

AF:

0.212

Gnomad4 ASJ

AF:

0.217

Gnomad4 EAS

AF:

0.221

Gnomad4 SAS

AF:

0.207

Gnomad4 FIN

AF:

0.252

Gnomad4 NFE

AF:

0.240

Gnomad4 OTH

AF:

0.240

Alfa

AF:

0.239

Hom.:

10362

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

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 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. -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2018	- -
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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

6.2

DANN

Benign

0.72

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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