dbSNP rs10988526: TOR1A:c.445-22G>A (chr9-129818942-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0670

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

early-onset generalized limb-onset dystonia
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
arthrogryposis multiplex congenita 5
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

TOR1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000113.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOR1A	NM_000113.3	MANE Select	c.445-22G>A		intron	N/A	NP_000104.1	O14656-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TOR1A	ENST00000351698.5	TSL:1 MANE Select	c.445-22G>A	intron	N/A	ENSP00000345719.4	O14656-1
TOR1A	ENST00000651202.1		c.541-22G>A	intron	N/A	ENSP00000498222.1	A0A494BZT7
TOR1A	ENST00000473604.2	TSL:5	n.555-22G>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00892

AC:

1357

AN:

152164

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0113

AC XY:

8180

AN XY:

724956

show subpopulations

African (AFR)

AF:

0.00224

AC:

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:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0124

AC:

13754

AN:

1111592

Other (OTH)

AF:

0.0101

AC:

611

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

859

1718

2578

3437

4296

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

460

920

1380

1840

2300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00890

AC:

1356

AN:

152282

Hom.:

Cov.:

AF XY:

0.00841

AC XY:

626

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00250

AC:

104

AN:

41570

American (AMR)

AF:

0.00399

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00720

AC:

AN:

3470

East Asian (EAS)

AF:

0.0123

AC:

AN:

5186

South Asian (SAS)

AF:

0.00622

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0125

AC:

133

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0136

AC:

925

AN:

68022

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

136

203

271

339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0120

Hom.:

Bravo

AF:

0.00779

Asia WGS

AF:

0.00953

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

8.3

(source)

DANN

Benign

0.88

PhyloP100

-0.067

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over