9-129813558-C-A

Variant names:

• chr9-129813558-C-A
• rs199964594
• NM_000113.3:c.*414G>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.*414G>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 0.0921 in 255,204 control chromosomes in the GnomAD database, including 1,089 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (550 hom., cov: 32)
  • Exomes 𝑓: 0.11 (539 hom.)
• Consequence: TOR1A NM_000113.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00400
• Publications: 0 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 9-129813558-C-A is Benign according to our data. Variant chr9-129813558-C-A is described in ClinVar as [Benign]. Clinvar id is 365225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOR1A	NM_000113.3	c.*414G>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.*414G>T		3_prime_UTR_variant	Exon 5 of 5	1	NM_000113.3	ENSP00000345719.4
TOR1A	ENST00000651202.1	c.*681G>T		3_prime_UTR_variant	Exon 6 of 6			ENSP00000498222.1
TOR1A	ENST00000474192.1	n.*50G>T		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0793 AC: 11376 AN: 143452 Hom.: 549 Cov.: 32

Gnomad AFR AF: 0.0182

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0857

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.0665

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.0690

Gnomad NFE AF: 0.0970

Gnomad OTH AF: 0.0909

GnomAD4 exome AF: 0.109 AC: 12134 AN: 111644 Hom.: 539 Cov.: 0 AF XY: 0.109 AC XY: 6686 AN XY: 61284

African (AFR) AF: 0.0221 AC: 49 AN: 2222

American (AMR) AF: 0.0933 AC: 362 AN: 3878

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 277 AN: 2588

East Asian (EAS) AF: 0.0676 AC: 270 AN: 3992

South Asian (SAS) AF: 0.126 AC: 2951 AN: 23420

European-Finnish (FIN) AF: 0.148 AC: 864 AN: 5848

Middle Eastern (MID) AF: 0.0505 AC: 19 AN: 376

European-Non Finnish (NFE) AF: 0.105 AC: 6721 AN: 63908

Other (OTH) AF: 0.115 AC: 621 AN: 5412

GnomAD4 genome AF: 0.0793 AC: 11379 AN: 143560 Hom.: 550 Cov.: 32 AF XY: 0.0836 AC XY: 5897 AN XY: 70516

African (AFR) AF: 0.0182 AC: 709 AN: 39030

American (AMR) AF: 0.0855 AC: 1258 AN: 14716

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 346 AN: 3250

East Asian (EAS) AF: 0.0668 AC: 325 AN: 4862

South Asian (SAS) AF: 0.136 AC: 645 AN: 4728

European-Finnish (FIN) AF: 0.159 AC: 1618 AN: 10178

Middle Eastern (MID) AF: 0.0699 AC: 19 AN: 272

European-Non Finnish (NFE) AF: 0.0970 AC: 6174 AN: 63626

Other (OTH) AF: 0.0943 AC: 190 AN: 2014

Alfa AF: 0.184 Hom.: 1245

Bravo AF: 0.0652

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Early-onset generalized limb-onset dystonia Benign:1

Jan 13, 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	1.7
DANN	Benign	0.70
PhyloP100		0.0040
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: rs199964594; hg19: chr9-132575837;