Genetic Variant WARS2:p.Trp13Gly (chr1-119140608-A-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PS3PM5PP5BP4

The NM_015836.4(WARS2):c.37T>G(p.Trp13Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,613,944 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV001142303: Functional studies demonstrate that c.37T>G has affected a mitochondrial signal peptide (SP) leading to mislocalization of the mutant protein in the cells. PMID:28236339" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W13R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0031 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0036 ( 22 hom. )

Consequence

WARS2
NM_015836.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:16U:4B:2

Conservation

PhyloP100: -0.145

Publications

25 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 links:

WARS2-AS1 (HGNC:40612): (WARS2 antisense RNA 1)

WARS2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001142303: Functional studies demonstrate that c.37T>G has affected a mitochondrial signal peptide (SP) leading to mislocalization of the mutant protein in the cells. PMID: 28236339; SCV001445976: "In vitro functional studies provide some evidence that the variant may impact protein function." PMID:29120065, 28236339; SCV006583096: "Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product." PMID: 28236339, 29120065; SCV003933944: Several publications report experimental evidence evaluating an impact on protein function and these studies showed that the variant results in decreased (but not absent) mitochondrial localization in vitro (Musante_2017), and reduced WARS2 protein levels, with impaired mitochondrial respiratory chain activity in fibroblasts derived from compound heterozygous patients (e.g. Burke_2018, Martinelli_2020, Skorvanek_2022). PMID:33619735, 29120065, 31970218, 35074316, 32120303, 28236339, 30831263, 39073549, 34890876; SCV004109532: "In vitro study showed this variant may affect the mitochondrial localization signal (Musante et al. 2017. PubMed ID: 28236339)."; SCV004847426: "In vitro studies provide some evidence that this variant impacts protein function by impairing mitochondrial localization and a reduction of protein level and consequently affecting mitochondrial respiratory chain activity (Musante 2017 PMID: 28236339, Burke 2018 PMID: 29120065)"

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-119140608-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1947813.

PP5

Variant 1-119140608-A-C is Pathogenic according to our data. Variant chr1-119140608-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 440915.

BP4

Computational evidence support a benign effect (MetaRNN=0.0043417513). . Strength limited to SUPPORTING due to the PP5.

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.37T>G	p.Trp13Gly	missense	Exon 1 of 6	NP_056651.1	Q9UGM6-1
WARS2	NM_001378228.1		c.37T>G	p.Trp13Gly	missense	Exon 1 of 6	NP_001365157.1	B7Z6G7
WARS2	NM_001378229.1		c.37T>G	p.Trp13Gly	missense	Exon 1 of 5	NP_001365158.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WARS2	ENST00000235521.5	TSL:1 MANE Select	c.37T>G	p.Trp13Gly	missense	Exon 1 of 6	ENSP00000235521.4	Q9UGM6-1
WARS2	ENST00000369426.9	TSL:1	c.37T>G	p.Trp13Gly	missense	Exon 1 of 6	ENSP00000358434.5	Q9UGM6-2
WARS2-AS1	ENST00000425884.7	TSL:1	n.213A>C		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes

AF:

0.00315

AC:

480

AN:

152276

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000844

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00419

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.000470

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00489

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00322

AC:

809

AN:

250992

AF XY:

0.00352

show subpopulations

Gnomad AFR exome

AF:

0.000555

Gnomad AMR exome

AF:

0.00357

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000695

Gnomad NFE exome

AF:

0.00436

Gnomad OTH exome

AF:

0.00636

GnomAD4 exome

AF:

0.00363

AC:

5311

AN:

1461550

Hom.:

Cov.:

AF XY:

0.00372

AC XY:

2703

AN XY:

727072

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33468

American (AMR)

AF:

0.00418

AC:

187

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00119

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00369

AC:

318

AN:

86218

European-Finnish (FIN)

AF:

0.000880

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00780

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00398

AC:

4423

AN:

1111822

Other (OTH)

AF:

0.00404

AC:

244

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

273

547

820

1094

1367

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

304

456

608

760

<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:

0.00315

AC:

480

AN:

152394

Hom.:

Cov.:

AF XY:

0.00305

AC XY:

227

AN XY:

74520

show subpopulations

African (AFR)

AF:

0.000841

AC:

AN:

41604

American (AMR)

AF:

0.00418

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00393

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000470

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00489

AC:

333

AN:

68040

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

122

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00399

Hom.:

Bravo

AF:

0.00300

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.00331

AC:

402

EpiCase

AF:

0.00616

EpiControl

AF:

0.00510

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (7)

Parkinsonism-dystonia 3, childhood-onset (5)

not provided (4)

WARS2-related disorder (3)

Inborn genetic diseases (1)

Neurodevelopmental disorder (1)

Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures;C5676913:Parkinsonism-dystonia 3, childhood-onset (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.11

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.63

M_CAP

Benign

0.0056

MetaRNN

Benign

0.0043

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PhyloP100

-0.14

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.74

REVEL

Benign

0.12

Sift

Benign

0.081

Sift4G

Uncertain

0.016

Polyphen

0.0010

Vest4

0.43

MVP

0.25

MPC

0.74

ClinPred

0.037

GERP RS

0.72

PromoterAI

-0.19

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.17

gMVP

0.62

Mutation Taster

=87/13

disease causing (ClinVar)

(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