rs3790549

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015836.4(WARS2):c.799G>C(p.Ala267Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0494 in 1,614,182 control chromosomes in the GnomAD database, including 2,726 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.066 ( 453 hom., cov: 33)

Exomes 𝑓: 0.048 ( 2273 hom. )

Consequence

WARS2
NM_015836.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.37

Publications

19 publications found

Variant links:

Genes affected

WARS2 (HGNC:12730): (tryptophanyl tRNA synthetase 2, mitochondrial) Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Two forms of tryptophanyl-tRNA synthetase exist, a cytoplasmic form, named WARS, and a mitochondrial form, named WARS2. This gene encodes the mitochondrial tryptophanyl-tRNA synthetase. Two alternative transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

WARS2 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

WARS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020585656).

BP6

Variant 1-119033195-C-G is Benign according to our data. Variant chr1-119033195-C-G is described in ClinVar as Benign. ClinVar VariationId is 1169497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015836.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WARS2	NM_015836.4	MANE Select	c.799G>C	p.Ala267Pro	missense	Exon 6 of 6	NP_056651.1	Q9UGM6-1
WARS2	NM_001378226.1		c.730G>C	p.Ala244Pro	missense	Exon 7 of 7	NP_001365155.1
WARS2	NM_001378227.1		c.730G>C	p.Ala244Pro	missense	Exon 8 of 8	NP_001365156.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WARS2	ENST00000235521.5	TSL:1 MANE Select	c.799G>C	p.Ala267Pro	missense	Exon 6 of 6	ENSP00000235521.4	Q9UGM6-1
WARS2	ENST00000369426.9	TSL:1	c.*165G>C		3_prime_UTR	Exon 6 of 6	ENSP00000358434.5	Q9UGM6-2
WARS2	ENST00000928547.1		c.862G>C	p.Ala288Pro	missense	Exon 7 of 7	ENSP00000598606.1

Frequencies

GnomAD3 genomes

AF:

0.0661

AC:

10054

AN:

152212

Hom.:

447

Cov.:

show subpopulations

Gnomad AFR

AF:

0.102

Gnomad AMI

AF:

0.0537

Gnomad AMR

AF:

0.0529

Gnomad ASJ

AF:

0.0395

Gnomad EAS

AF:

0.197

Gnomad SAS

AF:

0.0610

Gnomad FIN

AF:

0.0301

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0446

Gnomad OTH

AF:

0.0635

GnomAD2 exomes

AF:

0.0571

AC:

14338

AN:

250910

AF XY:

0.0554

show subpopulations

Gnomad AFR exome

AF:

0.101

Gnomad AMR exome

AF:

0.0311

Gnomad ASJ exome

AF:

0.0364

Gnomad EAS exome

AF:

0.188

Gnomad FIN exome

AF:

0.0347

Gnomad NFE exome

AF:

0.0445

Gnomad OTH exome

AF:

0.0502

GnomAD4 exome

AF:

0.0477

AC:

69684

AN:

1461852

Hom.:

2273

Cov.:

AF XY:

0.0478

AC XY:

34766

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.107

AC:

3572

AN:

33480

American (AMR)

AF:

0.0332

AC:

1483

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0373

AC:

974

AN:

26136

East Asian (EAS)

AF:

0.178

AC:

7079

AN:

39700

South Asian (SAS)

AF:

0.0560

AC:

4831

AN:

86256

European-Finnish (FIN)

AF:

0.0354

AC:

1891

AN:

53384

Middle Eastern (MID)

AF:

0.0674

AC:

389

AN:

5768

European-Non Finnish (NFE)

AF:

0.0413

AC:

45967

AN:

1112010

Other (OTH)

AF:

0.0579

AC:

3498

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

4944

9888

14833

19777

24721

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1826

3652

5478

7304

9130

<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:

0.0661

AC:

10072

AN:

152330

Hom.:

453

Cov.:

AF XY:

0.0649

AC XY:

4831

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.102

AC:

4243

AN:

41568

American (AMR)

AF:

0.0529

AC:

809

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0395

AC:

137

AN:

3472

East Asian (EAS)

AF:

0.196

AC:

1017

AN:

5178

South Asian (SAS)

AF:

0.0608

AC:

294

AN:

4832

European-Finnish (FIN)

AF:

0.0301

AC:

320

AN:

10624

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0446

AC:

3034

AN:

68028

Other (OTH)

AF:

0.0718

AC:

152

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

472

944

1417

1889

2361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<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:

0.0507

Hom.:

187

Bravo

AF:

0.0674

TwinsUK

AF:

0.0440

AC:

163

ALSPAC

AF:

0.0397

AC:

153

ESP6500AA

AF:

0.103

AC:

454

ESP6500EA

AF:

0.0431

AC:

371

ExAC

AF:

0.0568

AC:

6901

Asia WGS

AF:

0.145

AC:

505

AN:

3478

EpiCase

AF:

0.0469

EpiControl

AF:

0.0452

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.067

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.25

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0021

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.57

PhyloP100

2.4

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.2

REVEL

Benign

0.096

Sift

Benign

0.15

Sift4G

Benign

0.14

Polyphen

0.51

Vest4

0.080

MPC

1.0

ClinPred

0.023

GERP RS

4.9

Varity_R

0.64

gMVP

0.55

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over