rs10988526

Variant names:

• chr9-129818942-C-T
• rs10988526
• NM_000113.3:c.445-22G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000113.3(TOR1A):​c.445-22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,609,036 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (9 hom., cov: 31)
  • Exomes 𝑓: 0.011 (121 hom.)
• Consequence: TOR1A NM_000113.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0670
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 9-129818942-C-T is Benign according to our data. Variant chr9-129818942-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0089 (1356/152282) while in subpopulation NFE AF = 0.0136 (925/68022). AF 95% confidence interval is 0.0129. There are 9 homozygotes in GnomAd4. There are 626 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOR1A	NM_000113.3	c.445-22G>A		intron_variant	Intron 2 of 4	ENST00000351698.5	NP_000104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOR1A	ENST00000351698.5	c.445-22G>A		intron_variant	Intron 2 of 4	1	NM_000113.3	ENSP00000345719.4
TOR1A	ENST00000651202.1	c.541-22G>A		intron_variant	Intron 2 of 5			ENSP00000498222.1
TOR1A	ENST00000473604.2	n.555-22G>A		intron_variant	Intron 2 of 3	5
TOR1A	ENST00000474192.1	n.-161G>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00892 AC: 1357 AN: 152164 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00400

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.0121

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.0125

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00974 AC: 2389 AN: 245186 AF XY: 0.00965

Gnomad AFR exome AF: 0.00249

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00609

Gnomad EAS exome AF: 0.00999

Gnomad FIN exome AF: 0.0155

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.00955

GnomAD4 exome AF: 0.0114 AC: 16663 AN: 1456754 Hom.: 121 Cov.: 33 AF XY: 0.0113 AC XY: 8180 AN XY: 724956

African (AFR) AF: 0.00224 AC: 75 AN: 33462

American (AMR) AF: 0.00271 AC: 121 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00562 AC: 147 AN: 26134

East Asian (EAS) AF: 0.0166 AC: 660 AN: 39686

South Asian (SAS) AF: 0.00563 AC: 485 AN: 86206

European-Finnish (FIN) AF: 0.0161 AC: 785 AN: 48874

Middle Eastern (MID) AF: 0.00435 AC: 25 AN: 5746

European-Non Finnish (NFE) AF: 0.0124 AC: 13754 AN: 1111592

Other (OTH) AF: 0.0101 AC: 611 AN: 60338

GnomAD4 genome AF: 0.00890 AC: 1356 AN: 152282 Hom.: 9 Cov.: 31 AF XY: 0.00841 AC XY: 626 AN XY: 74460

African (AFR) AF: 0.00250 AC: 104 AN: 41570

American (AMR) AF: 0.00399 AC: 61 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3470

East Asian (EAS) AF: 0.0123 AC: 64 AN: 5186

South Asian (SAS) AF: 0.00622 AC: 30 AN: 4824

European-Finnish (FIN) AF: 0.0125 AC: 133 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0136 AC: 925 AN: 68022

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.0120 Hom.: 2

Bravo AF: 0.00779

Asia WGS AF: 0.00953 AC: 33 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 09, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.3
DANN	Benign	0.88
PhyloP100		-0.067
Mutation Taster		=100/0	polymorphism

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: rs10988526; hg19: chr9-132581221;