Genetic Variant TARS3:p.Ala96Gly (chr15-101724101-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_152334.3(TARS3):c.287C>G(p.Ala96Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 1,363,024 control chromosomes in the GnomAD database, including 68,648 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A96D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.32 ( 8876 hom., cov: 34)

Exomes 𝑓: 0.29 ( 59772 hom. )

Consequence

TARS3
NM_152334.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0700

Publications

23 publications found

Variant links:

Genes affected

TARS3 (HGNC:24728): (threonyl-tRNA synthetase 3) Predicted to enable threonine-tRNA ligase activity. Predicted to be involved in threonyl-tRNA aminoacylation. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

TARS3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.1794356E-6).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TARS3	NM_152334.3 link	c.287C>G	p.Ala96Gly	missense_variant	Exon 1 of 19	ENST00000335968.8	NP_689547.2	A2RTX5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TARS3	ENST00000335968.8 link	c.287C>G	p.Ala96Gly	missense_variant	Exon 1 of 19	1	NM_152334.3	ENSP00000338093.3	A2RTX5-1
TARS3	ENST00000539112.5 link	n.287C>G		non_coding_transcript_exon_variant	Exon 1 of 20	1		ENSP00000439899.1	B7ZLP8
TARS3	ENST00000615656.1 link	c.287C>G	p.Ala96Gly	missense_variant	Exon 1 of 19	5		ENSP00000478827.1	B7ZLP8

Frequencies

GnomAD3 genomes

AF:

0.318

AC:

48360

AN:

152088

Hom.:

8871

Cov.:

show subpopulations

Gnomad AFR

AF:

0.255

Gnomad AMI

AF:

0.308

Gnomad AMR

AF:

0.419

Gnomad ASJ

AF:

0.400

Gnomad EAS

AF:

0.814

Gnomad SAS

AF:

0.537

Gnomad FIN

AF:

0.321

Gnomad MID

AF:

0.436

Gnomad NFE

AF:

0.274

Gnomad OTH

AF:

0.344

GnomAD2 exomes

AF:

0.425

AC:

8145

AN:

19156

AF XY:

0.414

show subpopulations

Gnomad AFR exome

AF:

0.249

Gnomad AMR exome

AF:

0.552

Gnomad ASJ exome

AF:

0.439

Gnomad EAS exome

AF:

0.837

Gnomad FIN exome

AF:

0.316

Gnomad NFE exome

AF:

0.290

Gnomad OTH exome

AF:

0.430

GnomAD4 exome

AF:

0.294

AC:

355973

AN:

1210824

Hom.:

59772

Cov.:

AF XY:

0.300

AC XY:

175629

AN XY:

585672

show subpopulations

African (AFR)

AF:

0.251

AC:

6112

AN:

24318

American (AMR)

AF:

0.503

AC:

6511

AN:

12950

Ashkenazi Jewish (ASJ)

AF:

0.399

AC:

6764

AN:

16970

East Asian (EAS)

AF:

0.846

AC:

23395

AN:

27662

South Asian (SAS)

AF:

0.512

AC:

27552

AN:

53804

European-Finnish (FIN)

AF:

0.311

AC:

9564

AN:

30788

Middle Eastern (MID)

AF:

0.439

AC:

1567

AN:

3568

European-Non Finnish (NFE)

AF:

0.260

AC:

257634

AN:

990976

Other (OTH)

AF:

0.339

AC:

16874

AN:

49788

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

13136

26272

39408

52544

65680

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9484

18968

28452

37936

47420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.318

AC:

48382

AN:

152200

Hom.:

8876

Cov.:

AF XY:

0.329

AC XY:

24501

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.255

AC:

10588

AN:

41548

American (AMR)

AF:

0.420

AC:

6423

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.400

AC:

1389

AN:

3470

East Asian (EAS)

AF:

0.814

AC:

4202

AN:

5164

South Asian (SAS)

AF:

0.538

AC:

2597

AN:

4830

European-Finnish (FIN)

AF:

0.321

AC:

3400

AN:

10608

Middle Eastern (MID)

AF:

0.424

AC:

123

AN:

290

European-Non Finnish (NFE)

AF:

0.274

AC:

18657

AN:

67970

Other (OTH)

AF:

0.342

AC:

723

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1661

3323

4984

6646

8307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

492

984

1476

1968

2460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.292

Hom.:

856

Bravo

AF:

0.326

TwinsUK

AF:

0.251

AC:

932

ALSPAC

AF:

0.270

AC:

1039

ESP6500AA

AF:

0.155

AC:

440

ESP6500EA

AF:

0.198

AC:

1203

ExAC

AF:

0.273

AC:

23064

Asia WGS

AF:

0.622

AC:

2156

AN:

3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

8.7

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.019

T;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.35

T;T

MetaRNN

Benign

0.0000012

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.4

L;.

PhyloP100

-0.070

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.62

N;.

REVEL

Benign

0.050

Sift

Benign

0.16

T;.

Sift4G

Benign

0.13

T;T

Polyphen

0.0

B;.

Vest4

0.068

MPC

0.92

ClinPred

0.0091

GERP RS

1.4

PromoterAI

-0.069

Neutral

(source)

Varity_R

0.039

gMVP

0.14

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over