rs1182

Variant names:

• chr9-129813781-C-A
• rs1182
• NM_000113.3:c.*191G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000113.3(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 NM_000113.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.16
• Publications: 38 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
TOR1A	NM_000113.3	c.*191G>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000351698.5	NP_000104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOR1A	ENST00000351698.5	c.*191G>T		3_prime_UTR_variant	Exon 5 of 5	1	NM_000113.3	ENSP00000345719.4
TOR1A	ENST00000474192.1	n.774G>T		non_coding_transcript_exon_variant	Exon 3 of 3	3
TOR1A	ENST00000651202.1	c.*458G>T		3_prime_UTR_variant	Exon 6 of 6			ENSP00000498222.1

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

African (AFR) AF: 0.0483 AC: 842 AN: 17446

American (AMR) AF: 0.165 AC: 5258 AN: 31896

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 3647 AN: 17686

East Asian (EAS) AF: 0.238 AC: 7654 AN: 32176

South Asian (SAS) AF: 0.186 AC: 10741 AN: 57596

European-Finnish (FIN) AF: 0.233 AC: 7524 AN: 32258

Middle Eastern (MID) AF: 0.181 AC: 461 AN: 2554

European-Non Finnish (NFE) AF: 0.218 AC: 91574 AN: 420712

Other (OTH) AF: 0.207 AC: 6864 AN: 33226

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

African (AFR) AF: 0.0490 AC: 2035 AN: 41552

American (AMR) AF: 0.183 AC: 2797 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 685 AN: 3472

East Asian (EAS) AF: 0.200 AC: 1034 AN: 5160

South Asian (SAS) AF: 0.189 AC: 911 AN: 4824

European-Finnish (FIN) AF: 0.247 AC: 2619 AN: 10590

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.219 AC: 14867 AN: 67988

Other (OTH) AF: 0.192 AC: 407 AN: 2116

Alfa AF: 0.199 Hom.: 714

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

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: 25203860, 19202559, 17130424, 23460578, 23058565, 19642110) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dystonic disorder Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.46
DANN	Benign	0.67
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1182; hg19: chr9-132576060;