rs1182

Positions:

• chr9-129813781-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000351698.5(TOR1A):​c.*191G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 797,746 control chromosomes in the GnomAD database, including 17,288 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2593 hom., cov: 32)
  • Exomes 𝑓: 0.21 (14695 hom.)
• Consequence: TOR1A ENST00000351698.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.16

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 9-129813781-C-A is Benign according to our data. Variant chr9-129813781-C-A is described in ClinVar as [Benign]. Clinvar id is 365229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOR1A	NM_000113.3	c.*191G>T		3_prime_UTR_variant	5/5	ENST00000351698.5	NP_000104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOR1A	ENST00000351698.5	c.*191G>T		3_prime_UTR_variant	5/5	1	NM_000113.3	ENSP00000345719	P1
TOR1A	ENST00000651202.1	c.*458G>T		3_prime_UTR_variant	6/6			ENSP00000498222
TOR1A	ENST00000474192.1	n.774G>T		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25569 AN: 152078 Hom.: 2594 Cov.: 32

Gnomad AFR AF: 0.0491

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.190

GnomAD4 exome AF: 0.208 AC: 134565 AN: 645550 Hom.: 14695 Cov.: 9 AF XY: 0.208 AC XY: 70179 AN XY: 337912

Gnomad4 AFR exome AF: 0.0483

Gnomad4 AMR exome AF: 0.165

Gnomad4 ASJ exome AF: 0.206

Gnomad4 EAS exome AF: 0.238

Gnomad4 SAS exome AF: 0.186

Gnomad4 FIN exome AF: 0.233

Gnomad4 NFE exome AF: 0.218

Gnomad4 OTH exome AF: 0.207

GnomAD4 genome AF: 0.168 AC: 25568 AN: 152196 Hom.: 2593 Cov.: 32 AF XY: 0.170 AC XY: 12669 AN XY: 74408

Gnomad4 AFR AF: 0.0490

Gnomad4 AMR AF: 0.183

Gnomad4 ASJ AF: 0.197

Gnomad4 EAS AF: 0.200

Gnomad4 SAS AF: 0.189

Gnomad4 FIN AF: 0.247

Gnomad4 NFE AF: 0.219

Gnomad4 OTH AF: 0.192

Alfa AF: 0.202 Hom.: 711

Bravo AF: 0.157

Asia WGS AF: 0.220 AC: 763 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 2018	This variant is associated with the following publications: (PMID: 25203860, 19202559, 17130424, 23460578, 23058565, 19642110) -

Dystonic disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Early-onset generalized limb-onset dystonia Benign: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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.46
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1182; hg19: chr9-132576060;