9-129814233-G-T

Position:

• chr9-129814233-G-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.749-11C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,614,012 control chromosomes in the GnomAD database, including 501 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (36 hom., cov: 32)
  • Exomes 𝑓: 0.017 (465 hom.)
• Consequence: TOR1A NM_000113.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001530
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.587

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 (BayesDel_noAF=-0.79).
• BP6: Variant 9-129814233-G-T is Benign according to our data. Variant chr9-129814233-G-T is described in ClinVar as [Benign]. Clinvar id is 255137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-129814233-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.055 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOR1A	NM_000113.3	c.749-11C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000351698.5	NP_000104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOR1A	ENST00000351698.5	c.749-11C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000113.3	ENSP00000345719	P1
TOR1A	ENST00000651202.1	c.*17-11C>A		splice_polypyrimidine_tract_variant, intron_variant				ENSP00000498222
TOR1A	ENST00000474192.1	n.333-11C>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2024 AN: 152078 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.00413

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.0695

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0609

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.0173

GnomAD3 exomes AF: 0.0206 AC: 5169 AN: 251308 Hom.: 118 AF XY: 0.0237 AC XY: 3214 AN XY: 135856

Gnomad AFR exome AF: 0.00375

Gnomad AMR exome AF: 0.0135

Gnomad ASJ exome AF: 0.0608

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0649

Gnomad FIN exome AF: 0.00301

Gnomad NFE exome AF: 0.0162

Gnomad OTH exome AF: 0.0207

GnomAD4 exome AF: 0.0168 AC: 24505 AN: 1461816 Hom.: 465 Cov.: 31 AF XY: 0.0185 AC XY: 13426 AN XY: 727216

Gnomad4 AFR exome AF: 0.00394

Gnomad4 AMR exome AF: 0.0133

Gnomad4 ASJ exome AF: 0.0599

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0673

Gnomad4 FIN exome AF: 0.00326

Gnomad4 NFE exome AF: 0.0133

Gnomad4 OTH exome AF: 0.0192

GnomAD4 genome AF: 0.0133 AC: 2025 AN: 152196 Hom.: 36 Cov.: 32 AF XY: 0.0140 AC XY: 1045 AN XY: 74408

Gnomad4 AFR AF: 0.00426

Gnomad4 AMR AF: 0.0155

Gnomad4 ASJ AF: 0.0695

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0608

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.0147

Gnomad4 OTH AF: 0.0176

Alfa AF: 0.0119 Hom.: 4

Bravo AF: 0.0123

Asia WGS AF: 0.0260 AC: 93 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Dystonic disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Early-onset generalized limb-onset dystonia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.6
DANN	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.022
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

Other links and lift over

dbSNP: rs72755217; hg19: chr9-132576512;