Variant 1-179094094-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_022371.4(TOR3A):c.820A>C(p.Asn274His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TOR3A
NM_022371.4 missense, splice_region

Scores

Splicing: ADA: 0.2092

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.57

Variant links:

Genes affected

TOR3A (HGNC:11997): (torsin family 3 member A) Predicted to enable ATP binding activity. Located in endoplasmic reticulum lumen. [provided by Alliance of Genome Resources, Apr 2022]

TOR3A links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOR3A	NM_022371.4 linkuse as main transcript	c.820A>C	p.Asn274His	missense_variant, splice_region_variant	5/6	ENST00000367627.8	NP_071766.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOR3A	ENST00000367627.8 linkuse as main transcript	c.820A>C	p.Asn274His	missense_variant, splice_region_variant	5/6	1	NM_022371.4	ENSP00000356599	P1	Q9H497-1
TOR3A	ENST00000352445.10 linkuse as main transcript	c.820A>C	p.Asn274His	missense_variant, splice_region_variant	5/6	1		ENSP00000335351		Q9H497-2
TOR3A	ENST00000447595.1 linkuse as main transcript	c.496A>C	p.Asn166His	missense_variant, splice_region_variant	3/3	2		ENSP00000410195
TOR3A	ENST00000472001.1 linkuse as main transcript	n.615A>C		splice_region_variant, non_coding_transcript_exon_variant	5/5	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459576

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726012

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The c.820A>C (p.N274H) alteration is located in exon 5 (coding exon 5) of the TOR3A gene. This alteration results from a A to C substitution at nucleotide position 820, causing the asparagine (N) at amino acid position 274 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.57

D;.;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.069

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Benign

-0.72

MutationAssessor

Pathogenic

3.7

H;H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-4.6

D;D;D

REVEL

Uncertain

0.55

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

0.74

P;.;.

Vest4

0.95

MutPred

0.89

Loss of catalytic residue at N274 (P = 0.1183);Loss of catalytic residue at N274 (P = 0.1183);.;

MVP

0.80

MPC

0.71

ClinPred

0.99

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.65

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.21

dbscSNV1_RF

Benign

0.53

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over