chr9-129813518-A-T

Variant names:

• chr9-129813518-A-T
• rs1045441
• NM_000113.3:c.*454T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000113.3(TOR1A):​c.*454T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0779 in 278,610 control chromosomes in the GnomAD database, including 966 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.083 (589 hom., cov: 32)
  • Exomes 𝑓: 0.072 (377 hom.)
• Consequence: TOR1A NM_000113.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.129
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0892 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOR1A	NM_000113.3	c.*454T>A		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.*454T>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_000113.3	ENSP00000345719.4
TOR1A	ENST00000651202.1	c.*721T>A		3_prime_UTR_variant	Exon 6 of 6			ENSP00000498222.1
TOR1A	ENST00000474192.1	n.*90T>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0826 AC: 12548 AN: 151892 Hom.: 587 Cov.: 32

Gnomad AFR AF: 0.0917

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.0813

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.0774

Gnomad FIN AF: 0.0398

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0853

Gnomad OTH AF: 0.0891

GnomAD4 exome AF: 0.0722 AC: 9144 AN: 126600 Hom.: 377 Cov.: 0 AF XY: 0.0722 AC XY: 4958 AN XY: 68642

African (AFR) AF: 0.0804 AC: 226 AN: 2812

American (AMR) AF: 0.0698 AC: 296 AN: 4242

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 306 AN: 2814

East Asian (EAS) AF: 0.00320 AC: 15 AN: 4682

South Asian (SAS) AF: 0.0707 AC: 1686 AN: 23850

European-Finnish (FIN) AF: 0.0392 AC: 251 AN: 6406

Middle Eastern (MID) AF: 0.115 AC: 52 AN: 454

European-Non Finnish (NFE) AF: 0.0773 AC: 5813 AN: 75202

Other (OTH) AF: 0.0813 AC: 499 AN: 6138

GnomAD4 genome AF: 0.0826 AC: 12558 AN: 152010 Hom.: 589 Cov.: 32 AF XY: 0.0791 AC XY: 5874 AN XY: 74300

African (AFR) AF: 0.0916 AC: 3790 AN: 41372

American (AMR) AF: 0.0813 AC: 1241 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 429 AN: 3472

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5170

South Asian (SAS) AF: 0.0781 AC: 376 AN: 4816

European-Finnish (FIN) AF: 0.0398 AC: 422 AN: 10604

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.0853 AC: 5799 AN: 67998

Other (OTH) AF: 0.0877 AC: 185 AN: 2110

Alfa AF: 0.0778 Hom.: 76

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

-

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 12, 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	-0.83
CADD	Benign	2.5
DANN	Benign	0.80
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1045441; hg19: chr9-132575797;