NM_000113.3:c.*415_*416insG

Variant names:

• chr9-129813556-A-AC
• rs60745320
• NM_000113.3:c.*415_*416insG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0078 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (1 hom.)
• Consequence: TOR1A NM_000113.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.30
• Publications: 1 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 -10 ACMG points.

• BP6: Variant 9-129813556-A-AC is Benign according to our data. Variant chr9-129813556-A-AC is described in ClinVar as Likely_benign. ClinVar VariationId is 365222.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOR1A	NM_000113.3	MANE Select	c.*415_*416insG		3_prime_UTR	Exon 5 of 5	NP_000104.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOR1A	ENST00000351698.5	TSL:1 MANE Select	c.*415_*416insG		3_prime_UTR	Exon 5 of 5	ENSP00000345719.4
	TOR1A	ENST00000651202.1		c.*682_*683insG		3_prime_UTR	Exon 6 of 6	ENSP00000498222.1
	TOR1A	ENST00000474192.1	TSL:3	n.*51_*52insG		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00775 AC: 1175 AN: 151620 Hom.: 13 Cov.: 32

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: 88 AN: 148784 Hom.: 1 Cov.: 0 AF XY: 0.000508 AC XY: 41 AN XY: 80778

African (AFR) AF: 0.0174 AC: 65 AN: 3744

American (AMR) AF: 0.00124 AC: 6 AN: 4824

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3524

East Asian (EAS) AF: 0.000714 AC: 4 AN: 5602

South Asian (SAS) AF: 0.0000700 AC: 2 AN: 28576

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7392

Middle Eastern (MID) AF: 0.00192 AC: 1 AN: 522

European-Non Finnish (NFE) AF: 0.0000458 AC: 4 AN: 87374

Other (OTH) AF: 0.000830 AC: 6 AN: 7226

GnomAD4 genome AF: 0.00775 AC: 1176 AN: 151738 Hom.: 13 Cov.: 32 AF XY: 0.00770 AC XY: 572 AN XY: 74250

African (AFR) AF: 0.0265 AC: 1096 AN: 41312

American (AMR) AF: 0.00334 AC: 51 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5168

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67814

Other (OTH) AF: 0.00665 AC: 14 AN: 2106

Alfa AF: 0.00632 Hom.: 0

Bravo AF: 0.00880

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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 v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs60745320; hg19: chr9-132575835;