9-129813556-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000113.3(TOR1A):c.*416T>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 0.0161 in 300,488 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (30 hom., cov: 33)
  • Exomes 𝑓: 0.016 (22 hom.)
• Consequence: TOR1A NM_000113.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.161

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 9-129813556-A-C is Benign according to our data. Variant chr9-129813556-A-C is described in ClinVar as [Benign]. Clinvar id is 365223.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0163 (2479/151730) while in subpopulation NFE AF= 0.0218 (1478/67810). AF 95% confidence interval is 0.0209. There are 30 homozygotes in gnomad4. There are 1301 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 31 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOR1A	NM_000113.3	c.*416T>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.*416T>G		3_prime_UTR_variant	5/5	1	NM_000113.3	P1
TOR1A	ENST00000651202.1	c.*683T>G		3_prime_UTR_variant	6/6

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2483 AN: 151612 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.00398

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0205

Gnomad ASJ AF: 0.00376

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00808

Gnomad FIN AF: 0.0385

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0218

Gnomad OTH AF: 0.0197

GnomAD4 exome AF: 0.0158 AC: 2344 AN: 148758 Hom.: 22 Cov.: 0 AF XY: 0.0146 AC XY: 1178 AN XY: 80772

Gnomad4 AFR exome AF: 0.00214

Gnomad4 AMR exome AF: 0.0151

Gnomad4 ASJ exome AF: 0.00539

Gnomad4 EAS exome AF: 0.000179

Gnomad4 SAS exome AF: 0.00840

Gnomad4 FIN exome AF: 0.0284

Gnomad4 NFE exome AF: 0.0192

Gnomad4 OTH exome AF: 0.0144

GnomAD4 genome AF: 0.0163 AC: 2479 AN: 151730 Hom.: 30 Cov.: 33 AF XY: 0.0175 AC XY: 1301 AN XY: 74242

Gnomad4 AFR AF: 0.00397

Gnomad4 AMR AF: 0.0205

Gnomad4 ASJ AF: 0.00376

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00788

Gnomad4 FIN AF: 0.0385

Gnomad4 NFE AF: 0.0218

Gnomad4 OTH AF: 0.0195

Alfa AF: 0.0181 Hom.: 3

Bravo AF: 0.0148

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.87
Cadd	Benign	0.98
Dann	Benign	0.71

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: rs186581792; hg19: chr9-132575835;