rs1183

Variant names:

• chr9-129813758-G-C
• rs1183
• NM_000113.3:c.*214C>G

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.*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:3
• Conservation: PhyloP100: 0.224
• Publications: 12 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=-0.82).
• 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 rank	MANE	Protein	UniProt
TOR1A	NM_000113.3	c.*214C>G		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.*214C>G		3_prime_UTR_variant	Exon 5 of 5	1	NM_000113.3	ENSP00000345719.4
TOR1A	ENST00000474192.1	n.797C>G		non_coding_transcript_exon_variant	Exon 3 of 3	3
TOR1A	ENST00000651202.1	c.*481C>G		3_prime_UTR_variant	Exon 6 of 6			ENSP00000498222.1

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

African (AFR) AF: 0.0914 AC: 1292 AN: 14134

American (AMR) AF: 0.0603 AC: 1550 AN: 25710

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 1840 AN: 15276

East Asian (EAS) AF: 0.00205 AC: 64 AN: 31206

South Asian (SAS) AF: 0.0799 AC: 4019 AN: 50330

European-Finnish (FIN) AF: 0.0421 AC: 1271 AN: 30182

Middle Eastern (MID) AF: 0.122 AC: 259 AN: 2120

European-Non Finnish (NFE) AF: 0.0885 AC: 27271 AN: 308018

Other (OTH) AF: 0.0904 AC: 2540 AN: 28096

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

African (AFR) AF: 0.0910 AC: 3782 AN: 41560

American (AMR) AF: 0.0812 AC: 1242 AN: 15296

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

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5186

South Asian (SAS) AF: 0.0782 AC: 378 AN: 4832

European-Finnish (FIN) AF: 0.0400 AC: 425 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0853 AC: 5800 AN: 68034

Other (OTH) AF: 0.0888 AC: 188 AN: 2116

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.82
CADD	Benign	1.8
DANN	Benign	0.38
PhyloP100		0.22
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: rs1183; hg19: chr9-132576037;