rs1801968

Positions:

• chr9-129818622-C-G
• chr9-129818622-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000113.3(TOR1A):​c.646G>C​(p.Asp216His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,614,148 control chromosomes in the GnomAD database, including 15,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1065 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14201 hom.)
• Consequence: TOR1A NM_000113.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:2
• Conservation: PhyloP100: 1.30

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018074214).
• BP6: Variant 9-129818622-C-G is Benign according to our data. Variant chr9-129818622-C-G is described in ClinVar as [Benign]. Clinvar id is 5182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-129818622-C-G is described in Lovd as [Benign]. Variant chr9-129818622-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOR1A	NM_000113.3	c.646G>C	p.Asp216His	missense_variant	4/5	ENST00000351698.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOR1A	ENST00000351698.5	c.646G>C	p.Asp216His	missense_variant	4/5	1	NM_000113.3	P1
TOR1A	ENST00000651202.1	c.742G>C	p.Asp248His	missense_variant	4/6
TOR1A	ENST00000473604.2	n.756G>C		non_coding_transcript_exon_variant	4/4	5
TOR1A	ENST00000474192.1	n.63G>C		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15936 AN: 152154 Hom.: 1062 Cov.: 32

Gnomad AFR AF: 0.0261

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.0732

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.110

GnomAD3 exomes AF: 0.125 AC: 31486 AN: 251470 Hom.: 2219 AF XY: 0.129 AC XY: 17508 AN XY: 135910

Gnomad AFR exome AF: 0.0217

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.0827

Gnomad SAS exome AF: 0.145

Gnomad FIN exome AF: 0.162

Gnomad NFE exome AF: 0.135

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.136 AC: 198663 AN: 1461876 Hom.: 14201 Cov.: 33 AF XY: 0.136 AC XY: 99191 AN XY: 727242

Gnomad4 AFR exome AF: 0.0214

Gnomad4 AMR exome AF: 0.107

Gnomad4 ASJ exome AF: 0.195

Gnomad4 EAS exome AF: 0.0643

Gnomad4 SAS exome AF: 0.150

Gnomad4 FIN exome AF: 0.161

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.129

GnomAD4 genome AF: 0.105 AC: 15937 AN: 152272 Hom.: 1065 Cov.: 32 AF XY: 0.107 AC XY: 7987 AN XY: 74444

Gnomad4 AFR AF: 0.0260

Gnomad4 AMR AF: 0.105

Gnomad4 ASJ AF: 0.198

Gnomad4 EAS AF: 0.0732

Gnomad4 SAS AF: 0.151

Gnomad4 FIN AF: 0.165

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.110

Alfa AF: 0.135 Hom.: 1127

Bravo AF: 0.0969

TwinsUK AF: 0.141 AC: 521

ALSPAC AF: 0.140 AC: 541

ESP6500AA AF: 0.0275 AC: 121

ESP6500EA AF: 0.140 AC: 1203

ExAC AF: 0.123 AC: 14903

Asia WGS AF: 0.0950 AC: 329 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 31, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 25% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 23. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Early-onset generalized limb-onset dystonia Benign:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 14, 2018

This variant is associated with the following publications: (PMID: 31583275, 17503336, 26940431, 23405979, 18519876, 19380705, 23460578, 20669276, 16537570) -

Dystonic disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Early-onset generalized limb-onset dystonia;C5436453:Arthrogryposis multiplex congenita 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 01, 2021

- -

DYSTONIA 1, TORSION, MODIFIER OF Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Sep 15, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	0.039	P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.098
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.015	D
Polyphen		0.90	P
Vest4		0.12
MPC		1.0
ClinPred		0.036	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.082
gMVP		0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs1801968; hg19: chr9-132580901; COSMIC: COSV61029039; COSMIC: COSV61029039;