rs2296793

Variant names:

• chr9-129822779-G-A
• rs2296793
• NM_000113.3:c.246C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-129822779-G-A
• chr9-129822779-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000113.3(TOR1A):​c.246C>T​(p.Ala82Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,613,904 control chromosomes in the GnomAD database, including 45,524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4075 hom., cov: 32)
  • Exomes 𝑓: 0.24 (41449 hom.)
• Consequence: TOR1A NM_000113.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.50
• Publications: 43 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-129822779-G-A is Benign according to our data. Variant chr9-129822779-G-A is described in ClinVar as Benign. ClinVar VariationId is 255134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000113.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOR1A	NM_000113.3	MANE Select	c.246C>T	p.Ala82Ala	synonymous	Exon 2 of 5	NP_000104.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOR1A	ENST00000351698.5	TSL:1 MANE Select	c.246C>T	p.Ala82Ala	synonymous	Exon 2 of 5	ENSP00000345719.4
	TOR1A	ENST00000473084.1	TSL:1	n.265C>T		non_coding_transcript_exon	Exon 2 of 2
	TOR1A	ENST00000651202.1		c.342C>T	p.Ala114Ala	synonymous	Exon 2 of 6	ENSP00000498222.1

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34865 AN: 151944 Hom.: 4076 Cov.: 32

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.252

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.237

GnomAD2 exomes AF: 0.224 AC: 56225 AN: 251480 AF XY: 0.226

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.226

Gnomad EAS exome AF: 0.200

Gnomad FIN exome AF: 0.239

Gnomad NFE exome AF: 0.240

Gnomad OTH exome AF: 0.242

GnomAD4 exome AF: 0.237 AC: 346107 AN: 1461840 Hom.: 41449 Cov.: 34 AF XY: 0.236 AC XY: 171551 AN XY: 727218

African (AFR) AF: 0.216 AC: 7236 AN: 33478

American (AMR) AF: 0.180 AC: 8042 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 5887 AN: 26136

East Asian (EAS) AF: 0.256 AC: 10156 AN: 39700

South Asian (SAS) AF: 0.208 AC: 17967 AN: 86258

European-Finnish (FIN) AF: 0.238 AC: 12707 AN: 53418

Middle Eastern (MID) AF: 0.201 AC: 1157 AN: 5768

European-Non Finnish (NFE) AF: 0.242 AC: 268826 AN: 1111962

Other (OTH) AF: 0.234 AC: 14129 AN: 60396

GnomAD4 genome AF: 0.229 AC: 34877 AN: 152064 Hom.: 4075 Cov.: 32 AF XY: 0.229 AC XY: 17033 AN XY: 74324

African (AFR) AF: 0.219 AC: 9066 AN: 41452

American (AMR) AF: 0.212 AC: 3234 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 751 AN: 3468

East Asian (EAS) AF: 0.221 AC: 1145 AN: 5172

South Asian (SAS) AF: 0.207 AC: 997 AN: 4820

European-Finnish (FIN) AF: 0.252 AC: 2657 AN: 10560

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.240 AC: 16295 AN: 67984

Other (OTH) AF: 0.240 AC: 507 AN: 2114

Alfa AF: 0.237 Hom.: 15143

Bravo AF: 0.223

Asia WGS AF: 0.238 AC: 824 AN: 3478

EpiCase AF: 0.239

EpiControl AF: 0.246

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Dystonic disorder (1)
-	-	1	Early-onset generalized limb-onset dystonia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.2
DANN	Benign	0.72
PhyloP100		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs2296793; hg19: chr9-132585058; COSMIC: COSV61028714; COSMIC: COSV61028714;