rs80358235

Variant names:

• chr9-129813987-ATAATCTAACTTGGTGAAC-A
• rs80358235
• NM_000113.3:c.966_983delGTTCACCAAGTTAGATTA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM4

The NM_000113.3(TOR1A):​c.966_983delGTTCACCAAGTTAGATTA​(p.Phe323_Tyr328del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TOR1A NM_000113.3 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance no assertion criteria provided U:1 O:1
• Conservation: PhyloP100: 7.01
• Publications: 3 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: 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000113.3
• PM4: Nonframeshift variant in NON repetitive region in NM_000113.3.

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.966_983delGTTCACCAAGTTAGATTA	p.Phe323_Tyr328del	disruptive_inframe_deletion	Exon 5 of 5	NP_000104.1	O14656-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOR1A	ENST00000351698.5	TSL:1 MANE Select	c.966_983delGTTCACCAAGTTAGATTA	p.Phe323_Tyr328del	disruptive_inframe_deletion	Exon 5 of 5	ENSP00000345719.4	O14656-1
	TOR1A	ENST00000651202.1		c.*234_*251delGTTCACCAAGTTAGATTA		3_prime_UTR	Exon 6 of 6	ENSP00000498222.1	A0A494BZT7
	TOR1A	ENST00000474192.1	TSL:3	n.550_567delGTTCACCAAGTTAGATTA		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Dystonia, early-onset atypical, with myoclonic features (1)
-	-	-	Early-onset generalized limb-onset dystonia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.0
Mutation Taster		=9/191	disease causing (long InDel)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80358235; hg19: chr9-132576266;