9-129813556-A-C

Variant names:

• chr9-129813556-A-C
• rs186581792
• NM_000113.3:c.*416T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.161
• 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=-0.87).
• 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_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOR1A	NM_000113.3	c.*416T>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.*416T>G		3_prime_UTR_variant	Exon 5 of 5	1	NM_000113.3	ENSP00000345719.4
TOR1A	ENST00000651202.1	c.*683T>G		3_prime_UTR_variant	Exon 6 of 6			ENSP00000498222.1
TOR1A	ENST00000474192.1	n.*52T>G		downstream_gene_variant		3

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

African (AFR) AF: 0.00214 AC: 8 AN: 3744

American (AMR) AF: 0.0151 AC: 73 AN: 4824

Ashkenazi Jewish (ASJ) AF: 0.00539 AC: 19 AN: 3524

East Asian (EAS) AF: 0.000179 AC: 1 AN: 5602

South Asian (SAS) AF: 0.00840 AC: 240 AN: 28572

European-Finnish (FIN) AF: 0.0284 AC: 210 AN: 7390

Middle Eastern (MID) AF: 0.0153 AC: 8 AN: 522

European-Non Finnish (NFE) AF: 0.0192 AC: 1681 AN: 87356

Other (OTH) AF: 0.0144 AC: 104 AN: 7224

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

African (AFR) AF: 0.00397 AC: 164 AN: 41312

American (AMR) AF: 0.0205 AC: 312 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00376 AC: 13 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00788 AC: 38 AN: 4820

European-Finnish (FIN) AF: 0.0385 AC: 408 AN: 10602

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0218 AC: 1478 AN: 67810

Other (OTH) AF: 0.0195 AC: 41 AN: 2106

Alfa AF: 0.0181 Hom.: 3

Bravo AF: 0.0148

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	-0.87
CADD	Benign	0.98
DANN	Benign	0.71
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism

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: rs186581792; hg19: chr9-132575835;