rs2296793

Positions:

• chr9-129822779-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.50

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]

ACMG classification

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	UniProt
TOR1A	NM_000113.3	c.246C>T	p.Ala82=	synonymous_variant	2/5	ENST00000351698.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOR1A	ENST00000351698.5	c.246C>T	p.Ala82=	synonymous_variant	2/5	1	NM_000113.3	P1
TOR1A	ENST00000473084.1	n.265C>T		non_coding_transcript_exon_variant	2/2	1
TOR1A	ENST00000651202.1	c.342C>T	p.Ala114=	synonymous_variant	2/6
TOR1A	ENST00000473604.2	n.356C>T		non_coding_transcript_exon_variant	2/4	5

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34865 AN: 151944 Hom.: 4076 Cov.: 32

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

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.: 34 AF XY: 0.236 AC XY: 171551 AN XY: 727218

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.: 32 AF XY: 0.229 AC XY: 17033 AN XY: 74324

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 17, 2018

- -

Dystonic disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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

Other links and lift over

dbSNP: rs2296793; hg19: chr9-132585058; COSMIC: COSV61028714; COSMIC: COSV61028714;