rs1183

chr9-129813758-G-C

Variant summary

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

The NM_000113.3(TOR1A):c.*214C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0801 in 657,396 control chromosomes in the GnomAD database, including 2,431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (588 hom., cov: 33)
  • Exomes 𝑓: 0.079 (1843 hom.)
• Consequence: TOR1A NM_000113.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.224

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=-0.82).
• BP6: Variant 9-129813758-G-C is Benign according to our data. Variant chr9-129813758-G-C is described in ClinVar as [Benign]. Clinvar id is 365228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0886 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOR1A	NM_000113.3	c.*214C>G		3_prime_UTR_variant	5/5	ENST00000351698.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOR1A	ENST00000351698.5	c.*214C>G		3_prime_UTR_variant	5/5	1	NM_000113.3	P1
TOR1A	ENST00000651202.1	c.*481C>G		3_prime_UTR_variant	6/6
TOR1A	ENST00000474192.1	n.797C>G		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.0825 AC: 12551 AN: 152206 Hom.: 586 Cov.: 33

Gnomad AFR AF: 0.0911

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.0812

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.0775

Gnomad FIN AF: 0.0400

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0852

Gnomad OTH AF: 0.0903

GnomAD4 exome AF: 0.0794 AC: 40106 AN: 505072 Hom.: 1843 Cov.: 6 AF XY: 0.0801 AC XY: 21430 AN XY: 267620

Gnomad4 AFR exome AF: 0.0914

Gnomad4 AMR exome AF: 0.0603

Gnomad4 ASJ exome AF: 0.120

Gnomad4 EAS exome AF: 0.00205

Gnomad4 SAS exome AF: 0.0799

Gnomad4 FIN exome AF: 0.0421

Gnomad4 NFE exome AF: 0.0885

Gnomad4 OTH exome AF: 0.0904

GnomAD4 genome AF: 0.0825 AC: 12561 AN: 152324 Hom.: 588 Cov.: 33 AF XY: 0.0789 AC XY: 5877 AN XY: 74488

Gnomad4 AFR AF: 0.0910

Gnomad4 AMR AF: 0.0812

Gnomad4 ASJ AF: 0.124

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.0782

Gnomad4 FIN AF: 0.0400

Gnomad4 NFE AF: 0.0853

Gnomad4 OTH AF: 0.0888

Alfa AF: 0.0781 Hom.: 77

Bravo AF: 0.0856

Asia WGS AF: 0.0440 AC: 154 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 26, 2018

- -

Early-onset generalized limb-onset dystonia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.82
Cadd	Benign	1.8
Dann	Benign	0.38

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: rs1183; hg19: chr9-132576037;