Genetic Variant NM_000113.3:c.*415_*416insG (chr9-129813556-A-AC) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_000113.3(TOR1A):c.*415_*416insG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00421 in 300,522 control chromosomes in the GnomAD database, including 14 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0078 ( 13 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 1 hom. )

Consequence

TOR1A
NM_000113.3 3_prime_UTR

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.30

Publications

1 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: 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

TOR1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00775 (1176/151738) while in subpopulation AFR AF = 0.0265 (1096/41312). AF 95% confidence interval is 0.0252. There are 13 homozygotes in GnomAd4. There are 572 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOR1A	NM_000113.3 link	c.415_416insG		3_prime_UTR_variant	Exon 5 of 5	ENST00000351698.5	NP_000104.1	O14656-1B3KPA1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
TOR1A	ENST00000351698.5 link	c.415_416insG	3_prime_UTR_variant	Exon 5 of 5	1	NM_000113.3	ENSP00000345719.4	O14656-1
TOR1A	ENST00000651202.1 link	c.682_683insG	3_prime_UTR_variant	Exon 6 of 6			ENSP00000498222.1	A0A494BZT7
TOR1A	ENST00000474192.1 link	n.51_52insG	downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00775

AC:

1175

AN:

151620

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00335

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00672

GnomAD4 exome

AF:

0.000591

AC:

AN:

148784

Hom.:

Cov.:

AF XY:

0.000508

AC XY:

AN XY:

80778

show subpopulations

African (AFR)

AF:

0.0174

AC:

AN:

3744

American (AMR)

AF:

0.00124

AC:

AN:

4824

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3524

East Asian (EAS)

AF:

0.000714

AC:

AN:

5602

South Asian (SAS)

AF:

0.0000700

AC:

AN:

28576

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7392

Middle Eastern (MID)

AF:

0.00192

AC:

AN:

522

European-Non Finnish (NFE)

AF:

0.0000458

AC:

AN:

87374

Other (OTH)

AF:

0.000830

AC:

AN:

7226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00775

AC:

1176

AN:

151738

Hom.:

Cov.:

AF XY:

0.00770

AC XY:

572

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.0265

AC:

1096

AN:

41312

American (AMR)

AF:

0.00334

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.00116

AC:

AN:

5168

South Asian (SAS)

AF:

0.000415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67814

Other (OTH)

AF:

0.00665

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

104

157

209

261

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00632

Hom.:

Bravo

AF:

0.00880

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Early-onset generalized limb-onset dystonia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.3

Mutation Taster

=100/0

polymorphism

(source)

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

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NM_000113.3:c.415_416insG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over