chr1-119140608-A-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM5BP4_StrongBS1_SupportingBS2

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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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:12U:4B:2

Conservation

PhyloP100: -0.145

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-119140608-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3233281.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.0043417513).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00315 (480/152394) while in subpopulation NFE AF= 0.00489 (333/68040). AF 95% confidence interval is 0.00446. There are 0 homozygotes in gnomad4. There are 227 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WARS2	NM_015836.4 link	c.37T>G	p.Trp13Gly	missense_variant	Exon 1 of 6	ENST00000235521.5	NP_056651.1	Q9UGM6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WARS2	ENST00000235521.5 link	c.37T>G	p.Trp13Gly	missense_variant	Exon 1 of 6	1	NM_015836.4	ENSP00000235521.4		Q9UGM6-1
WARS2	ENST00000369426.9 link	c.37T>G	p.Trp13Gly	missense_variant	Exon 1 of 6	1		ENSP00000358434.5		Q9UGM6-2

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

GnomAD3 exomes

AF:

0.00322

AC:

809

AN:

250992

Hom.:

AF XY:

0.00352

AC XY:

478

AN XY:

135722

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 SAS exome

AF:

0.00379

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

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.00418

Gnomad4 ASJ exome

AF:

0.00119

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00369

Gnomad4 FIN exome

AF:

0.000880

Gnomad4 NFE exome

AF:

0.00398

Gnomad4 OTH exome

AF:

0.00404

GnomAD4 genome

AF:

0.00315

AC:

480

AN:

152394

Hom.:

Cov.:

AF XY:

0.00305

AC XY:

227

AN XY:

74520

show subpopulations

Gnomad4 AFR

AF:

0.000841

Gnomad4 AMR

AF:

0.00418

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00393

Gnomad4 FIN

AF:

0.000470

Gnomad4 NFE

AF:

0.00489

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00423

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:12Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Pathogenic:5Uncertain:1

Feb 18, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 09, 2025

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous p.Trp13Gly variant in WARS2 was identified by our study in the compound heterozygous state, along with another variant of unknown significance, in 1 individual with neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures. The variant has been reported in at least 11 individuals with neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (PMID: 29120065, 28236339, 32120303, 30831263, 31970218, 39073549, 31970218, 37107582), and segregated with disease in 3 affected relatives from 3 families (PMID: 34890876, PMID: 28236339). This variant has been identified in 0.4% (251/60006) of Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs139548132), and was detected in homozygosity in 22 individuals from various populations. There is evidence that this variant is hypomorphic and homozygosity is not expected to cause disease (PMID: 34890876, 39073549), which may explain the high allele frequency and level of homozygosity for this variant in gnomAD. This variant has also been reported in ClinVar (Variation ID: 440915). Of the 11 affected individuals, 5 were compound heterozygotes that carried a likely pathogenic variants in trans, which increases the likelihood that the p.Trp13Gly variant is pathogenic (PMID: 28236339, 37107582, 39073549). In vitro functional studies provide some evidence that the variant may impact protein function (PMID: 29120065, 28236339). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures. ACMG/AMP Criteria applied: PS3_moderate, PM3_strong, PP1 (Richards 2015). -

May 05, 2022

Baylor Genetics

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Feb 28, 2020

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

NM_015836.3:c.37T>G in the WARS2 gene has an allele frequency of 0.006 in other subpopulation in the gnomAD database. 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). It was detected in individual with autosomal recessive Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures, compound heterozygous with c.325delA (PMID: 28236339). Benign computational verdict because benign predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationTaster, PrimateAI, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PS3; PM3; BP4. -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Parkinsonism-dystonia 3, childhood-onset

Pathogenic:2Uncertain:2

Feb 18, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 01, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

May 05, 2022

Baylor Genetics

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Apr 20, 2021

Undiagnosed Diseases Network, NIH

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

WARS2-related disorder

Pathogenic:3

Oct 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: WARS2 c.37T>G (p.Trp13Gly) results in a non-conservative amino acid change in the N-terminal mitochondrial signal peptide (amino acids 1-18, UniProt) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0032 in 250992 control chromosomes in the gnomAD database, including 6 homozygotes. The occurrences in homozygote controls suggest that the variant is likely benign when found in homozygous state. However, this variant (c.37T>G) has been reported in the literature in several compound heterozygous individuals affected with WARS2-Related Disorders, including patients with infantile-onset Parkinsonism (e.g. Musante_2017, Burke_2018, Nogueira_2019, Hubers_2019, Martinelli_2002, Brunet_2021, Skorvanek_2022, Schneider_2024), in addition, pathogenic variants have been confirmed in trans in the majority of these individuals and the variant has been shown to segregate with disease in related individuals. These data suggest that the pathogenicity (severity and penetrance) of the variant is genotype-dependent, i.e. highly dependent on the variant observed in trans. 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). The presence of homozygotes in the gnomAD control population, as well as the many compound heterozygous patients found to harbor this variant, and functional evidence collectively suggest that this variant represents a hypomorphic allele and will cause disease when in trans with another pathogenic variant but will not cause disease in homozygous state (e.g. Skorvanek_2022, Ilinca_2022). The following publications have been ascertained in the context of this evaluation (PMIDs: 33619735, 29120065, 31970218, 35074316, 32120303, 28236339, 30831263, 39073549, 34890876). ClinVar contains an entry for this variant (Variation ID: 440915). Based on the evidence outlined above, the variant represents a hypomorphic allele that is subject to interallelic interactions, which in compound heterozygous state, together with other (more severe) variants in trans, can cause WARS2-Related Disorders, therefore, this variant was classified as pathogenic. -

Feb 24, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The WARS2 c.37T>G variant is predicted to result in the amino acid substitution p.Trp13Gly. The c.37T>G (p.Trp13Gly) variant has been described as a hypomorphic allele and reported in the compound heterozygous state in multiple unrelated families affected with intellectual disability or infantile onset leukoencephalopathy (Musante et al. 2017. PubMed ID: 28236339 ; Burke et al. 2018. PubMed ID: 29120065; Nogueira et al. 2019. PubMed ID: 30831263; Martinelli et al. 2020. PubMed ID: 32120303; Hubers et al. 2020. PubMed ID: 31970218; Skorvanek et al. 2022. PubMed ID: 34890876). In vitro study showed this variant may affect the mitochondrial localization signal (Musante et al. 2017. PubMed ID: 28236339). This variant is reported in 0.46% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including 6 homozygous individuals of unknown phenotype (http://gnomad.broadinstitute.org/variant/1-119683231-A-C), and is only expected to cause disease when found in trans (on the opposite chromosome) with a second more deleterious variant in this gene (Skorvanek et al. 2022. PubMed ID: 34890876). Based on the collective evidence, we interpret this variant to be a likely pathogenic variant. -

Jan 04, 2023

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:1Benign:2

Nov 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: flagged submission

Collection Method: clinical testing

- -

Dec 19, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28236339, 30920170, 33611074, 34890876, 32120303, 31970218, 33619735, 29120065, 30831263, 34958143, 35795805, 35872528, 33949708, 35074316, 37417438, 36539902, 37107582) -

Nov 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurodevelopmental disorder

Pathogenic:1

Jan 29, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Trp13Gly variant in WARS2 has been reported in the compound heterozygous state in >15 individuals with WARS2-associated disorders including infantile-onset parkinson's disease, dystonia and neurodevelopmental disorder. In at least 5 individuals, the p.Trp13Gly variant was identified along with another disease causing variant in WARS2 (Musante 2017 PMID: 28236339, Burke 2018 PMID: 29120065, Hubers 2019 PMID: 31970218, Nogueira 2019 PMID: 30831263, Martinelli 2020 PMID: 32120303, Brunet 2021 PMID: 33619735, Dzinovic 2022 PMID: 35872528, Gabriel 2022 PMID: 34958143, Skorvanek 2022 PMID: 34890876, Pauly 2023 PMID: 37107582). This variant segregated in 3 affected relatives from 2 families (Musante 2017 PMID: 28236339, Skorvanek 2022 PMID: 34890876). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 440915) and has been identified in 0.77% (47/6060) of Middle Eastern and 0.4% (251/60006) of Admixed Americans chromosomes including 22 total homozygotes by gnomAD (http://gnomad.broadinstitute.org, v4.0.0). 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) but computational prediction tools and conservation analyses suggest that this variant may not impact the protein. Since this variant has been identified in the homozygous state in multiple individuals in gnomAD, the variant most likely represents a hypomorphic allele and is only expected to cause disease when found in trans with a second more deleterious variant in this gene, such as a loss of function variant. It is not expected to cause disease in the homozygous state. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive WARS2 deficiency. ACMG/AMP Criteria applied: PM3_Strong, PP1_Strong, PS3_Supporting, BS4. -

Inborn genetic diseases

Uncertain:1

Apr 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

The c.37T>G (p.W13G) alteration is located in exon 1 (coding exon 1) of the WARS2 gene. This alteration results from a T to G substitution at nucleotide position 37, causing the tryptophan (W) at amino acid position 13 to be replaced by a glycine (G). 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

0.11

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.11

.;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.63

T;T

M_CAP

Benign

0.0056

MetaRNN

Benign

0.0043

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.74

N;N

REVEL

Benign

0.12

Sift

Benign

0.081

T;T

Sift4G

Uncertain

0.016

D;T

Polyphen

0.0010

.;B

Vest4

0.43

MVP

0.25

MPC

0.74

ClinPred

0.037

GERP RS

0.72

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.17

gMVP

0.62

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