1-150487499-G-A

Position:

chr1-150487499-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_025150.5(TARS2):c.49G>A(p.Ala17Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

TARS2
NM_025150.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.784

Variant links:

Genes affected

TARS2 (HGNC:30740): (threonyl-tRNA synthetase 2, mitochondrial) This gene encodes a member of the class-II aminoacyl-tRNA synthetase family. The encoded protein is a mitochondrial aminoacyl-tRNA synthetase. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 4. [provided by RefSeq, Dec 2012]

TARS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0586071).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TARS2	NM_025150.5 linkuse as main transcript	c.49G>A	p.Ala17Thr	missense_variant	1/18	ENST00000369064.8	NP_079426.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TARS2	ENST00000369064.8 linkuse as main transcript	c.49G>A	p.Ala17Thr	missense_variant	1/18	1	NM_025150.5	ENSP00000358060	P1	Q9BW92-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251446

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000154

AC:

225

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000139

AC XY:

101

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000182

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000767

Hom.:

Bravo

AF:

0.000110

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2022	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 17 of the TARS2 protein (p.Ala17Thr). This variant is present in population databases (rs367864616, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TARS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 559355). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 29, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2023

The c.49G>A (p.A17T) alteration is located in exon 1 (coding exon 1) of the TARS2 gene. This alteration results from a G to A substitution at nucleotide position 49, causing the alanine (A) at amino acid position 17 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Combined oxidative phosphorylation defect type 21

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 21, 2020

A heterozygous missense variant was identified, NM_025150.4(TARS2):c.49G>A in exon 1 of 18 of the TARS2 gene. This substitution is predicted to create a minor amino acid change from an alanine to a threonine at position 17 of the protein; NP_079426.2(TARS2):p.(Ala17Thr). The alanine at this position has low conservation (100 vertebrates, UCSC), and is not situated in a known functional domain (NCBI, PDB, UniProt). In silico software predicts this variant to be tolerated (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a global population frequency of 0.008% (22 heterozygotes, 0 homozygotes) with a European sub-population frequency of 0.01%. This variant has been previously reported in ClinVar as a VUS. Based on information available at the time of curation, this variant has been classified as a VUS with LOW CLINICAL RELEVANCE. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.023

.;T;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.70

T;T;T

M_CAP

Benign

0.0032

MetaRNN

Benign

0.059

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.6

L;L;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.74

N;N;.

REVEL

Benign

0.013

Sift

Benign

0.10

T;T;.

Sift4G

Benign

0.38

T;T;T

Polyphen

0.0020

.;B;.

Vest4

0.15

MVP

0.10

MPC

0.41

ClinPred

0.039

GERP RS

2.1

Varity_R

0.040

gMVP

0.29

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

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