rs1801968
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
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
NM_000113.3 missense
Scores
8
10
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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: 15936AN: 152154Hom.: 1062 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.125 AC: 31486AN: 251470Hom.: 2219 AF XY: 0.129 AC XY: 17508AN XY: 135910
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GnomAD4 exome AF: 0.136 AC: 198663AN: 1461876Hom.: 14201 Cov.: 33 AF XY: 0.136 AC XY: 99191AN XY: 727242
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GnomAD4 genome ? AF: 0.105 AC: 15937AN: 152272Hom.: 1065 Cov.: 32 AF XY: 0.107 AC XY: 7987AN XY: 74444
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ClinVar
Significance: Benign
Submissions summary: Benign:10Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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:2Other: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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
P
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at