NM_000113.3:c.646G>C

Variant names:

• chr9-129818622-C-G
• rs1801968
• NM_000113.3:c.646G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000113.3(TOR1A):​c.646G>C​(p.Asp216His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,614,148 control chromosomes in the GnomAD database, including 15,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1065 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14201 hom.)
• Consequence: TOR1A NM_000113.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:2
• Conservation: PhyloP100: 1.30
• Publications: 81 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018074214).
• BP6: Variant 9-129818622-C-G is Benign according to our data. Variant chr9-129818622-C-G is described in ClinVar as Benign. ClinVar VariationId is 5182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

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.646G>C	p.Asp216His	missense	Exon 4 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.646G>C	p.Asp216His	missense	Exon 4 of 5	ENSP00000345719.4	O14656-1
	TOR1A	ENST00000651202.1		c.742G>C	p.Asp248His	missense	Exon 4 of 6	ENSP00000498222.1	A0A494BZT7
	TOR1A	ENST00000473604.2	TSL:5	n.756G>C		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15936 AN: 152154 Hom.: 1062 Cov.: 32

Gnomad AFR AF: 0.0261

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.0732

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.110

GnomAD2 exomes AF: 0.125 AC: 31486 AN: 251470 AF XY: 0.129

Gnomad AFR exome AF: 0.0217

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.0827

Gnomad FIN exome AF: 0.162

Gnomad NFE exome AF: 0.135

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.136 AC: 198663 AN: 1461876 Hom.: 14201 Cov.: 33 AF XY: 0.136 AC XY: 99191 AN XY: 727242

African (AFR) AF: 0.0214 AC: 718 AN: 33480

American (AMR) AF: 0.107 AC: 4783 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 5090 AN: 26136

East Asian (EAS) AF: 0.0643 AC: 2553 AN: 39700

South Asian (SAS) AF: 0.150 AC: 12914 AN: 86258

European-Finnish (FIN) AF: 0.161 AC: 8576 AN: 53402

Middle Eastern (MID) AF: 0.127 AC: 732 AN: 5768

European-Non Finnish (NFE) AF: 0.140 AC: 155509 AN: 1112012

Other (OTH) AF: 0.129 AC: 7788 AN: 60396

GnomAD4 genome AF: 0.105 AC: 15937 AN: 152272 Hom.: 1065 Cov.: 32 AF XY: 0.107 AC XY: 7987 AN XY: 74444

African (AFR) AF: 0.0260 AC: 1080 AN: 41576

American (AMR) AF: 0.105 AC: 1599 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 686 AN: 3468

East Asian (EAS) AF: 0.0732 AC: 379 AN: 5178

South Asian (SAS) AF: 0.151 AC: 727 AN: 4830

European-Finnish (FIN) AF: 0.165 AC: 1746 AN: 10594

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.137 AC: 9343 AN: 68010

Other (OTH) AF: 0.110 AC: 233 AN: 2112

Alfa AF: 0.135 Hom.: 1127

Bravo AF: 0.0969

TwinsUK AF: 0.141 AC: 521

ALSPAC AF: 0.140 AC: 541

ESP6500AA AF: 0.0275 AC: 121

ESP6500EA AF: 0.140 AC: 1203

ExAC AF: 0.123 AC: 14903

Asia WGS AF: 0.0950 AC: 329 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Early-onset generalized limb-onset dystonia (3)
-	-	2	not provided (2)
-	-	1	Dystonic disorder (1)
-	-	1	Early-onset generalized limb-onset dystonia;C5436453:Arthrogryposis multiplex congenita 5 (1)
-	-	-	DYSTONIA 1, TORSION, MODIFIER OF (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.3
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.098
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.015	D
Polyphen		0.90	P
Vest4		0.12
MPC		1.0
ClinPred		0.036	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.082
gMVP		0.66
Mutation Taster		=84/16	polymorphism (auto)

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: rs1801968; hg19: chr9-132580901; COSMIC: COSV61029039; COSMIC: COSV61029039;