chr9-129818752-A-T

Position:

chr9-129818752-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000113.3(TOR1A):c.613T>A(p.Phe205Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,613,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

TOR1A
NM_000113.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:6O:1

Conservation

PhyloP100: 8.95

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOR1A	NM_000113.3 linkuse as main transcript	c.613T>A	p.Phe205Ile	missense_variant	3/5	ENST00000351698.5	NP_000104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOR1A	ENST00000351698.5 linkuse as main transcript	c.613T>A	p.Phe205Ile	missense_variant	3/5	1	NM_000113.3	ENSP00000345719	P1	O14656-1
TOR1A	ENST00000651202.1 linkuse as main transcript	c.709T>A	p.Phe237Ile	missense_variant	3/6			ENSP00000498222
TOR1A	ENST00000473604.2 linkuse as main transcript	n.723T>A		non_coding_transcript_exon_variant	3/4	5
TOR1A	ENST00000474192.1 linkuse as main transcript	n.30T>A		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000479

AC:

AN:

250734

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135604

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000477

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000238

AC:

348

AN:

1461154

Hom.:

Cov.:

AF XY:

0.000221

AC XY:

161

AN XY:

726934

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000569

Gnomad4 NFE exome

AF:

0.000306

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000125

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000179

Hom.:

Bravo

AF:

0.000113

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 19, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	TOR1A: PS3:Moderate, PS4:Moderate -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 24, 2024	Identified in a patient with late-onset focal dystonia in the published literature (PMID: 19955557); Observed with a TOR1A variant on the opposite allele (in trans) in a patient with developmental delay, movement disorder, and spasticity in published literature (PMID: 36757831); Published functional studies demonstrate a damaging effect: cell culture studies show the variant produced frequent inclusion bodies and affected the function of the TOR1A protein; in addition, in vitro studies demonstrate the variant had increased tendency to dimerize, showed altered nuclear morphology, and compromised neurite extension in human neuroblastoma cells (PMID: 19955557, 24930953); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27168150, 24862462, 24930953, 28432771, 31090117, 24931141, 32243914, 32289333, 19955557, 36757831, 20301665, 30877032, 31583275) -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 11, 2019	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Phe205Ile variant in TOR1A has been reported in 1 individual with late-onset focal dyston ia (Calakos 2010), but was also identified in 0.01% (13/129134) of European chro mosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction t ools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support that the variant impacts protein function (Het tich 2014). However, these types of assays may not accurately represent biologic al function. A knock-in mouse model suggests that this variant results in reduce d levels of the TOR1A protein (Bhagat 2016). Furthermore, homozygous p.Phe205Ile knock-in mice exhibit motor impairment and altered synaptic plasticity (Bhagat 2016). However, given that these phenotypes were only observed in homozygous ani mals, it remains unclear if this variant would be expected to cause autosomal do minant primary-onset dystonia. In summary, while there is suspicion for a pathog enic role, the clinical significance of the p.Phe205Ile variant is uncertain. AC MG/AMP Criteria applied: PS3_Moderate, PP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 05, 2024	Variant summary: TOR1A c.613T>A (p.Phe205Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250734 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TOR1A causing TOR1A Related Disorders, allowing no conclusion about variant significance. c.613T>A has been reported in the literature in individuals affected with TOR1A Related Disorders (e.g. Calakos_2010, Saffari_2023, Gustavsson_2017). These report(s) do not provide unequivocal conclusions about association of the variant with TOR1A Related Disorders. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in motor impairment in mice that are homozygous for the variant (Bhagat_2017). The following publications have been ascertained in the context of this evaluation (PMID: 27168150, 19955557, 30363439, 24930953, 31583275, 32243914, 36757831). ClinVar contains an entry for this variant (Variation ID: 18438). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Early-onset generalized limb-onset dystonia

Uncertain:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 07, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Dystonia 1, torsion, late-onset

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2014

- -

Dystonic disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 25, 2023

This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 205 of the TOR1A protein (p.Phe205Ile). This variant is present in population databases (rs267607134, gnomAD 0.01%). This missense change has been observed in individual(s) with late-onset focal dystonia (PMID: 19955557). ClinVar contains an entry for this variant (Variation ID: 18438). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TOR1A protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TOR1A function (PMID: 19955557, 24930953, 27168150, 32243914). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.65

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.055

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

-0.11

MutationAssessor

Pathogenic

3.7

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-5.4

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.91

MVP

0.78

MPC

1.2

ClinPred

0.98

GERP RS

6.1

Varity_R

0.89

gMVP

0.92

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over