chr1-119033056-T-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 10P and 2B. PM2PP5_Very_StrongBP4BS1_Supporting

The NM_015836.4(WARS2):c.938A>T(p.Lys313Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000498 in 1,614,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00052 ( 0 hom. )

Consequence

WARS2
NM_015836.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:1

Conservation

PhyloP100: 3.08

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-119033056-T-A is Pathogenic according to our data. Variant chr1-119033056-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 440917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-119033056-T-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.21516874). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000322 (49/152386) while in subpopulation NFE AF= 0.000632 (43/68040). AF 95% confidence interval is 0.000482. There are 0 homozygotes in gnomad4. There are 26 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WARS2	NM_015836.4 link	c.938A>T	p.Lys313Met	missense_variant	Exon 6 of 6	ENST00000235521.5	NP_056651.1	Q9UGM6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
WARS2	ENST00000235521.5 link	c.938A>T	p.Lys313Met	missense_variant	Exon 6 of 6	1	NM_015836.4	ENSP00000235521.4	Q9UGM6-1
WARS2	ENST00000369426 link	c.*304A>T		3_prime_UTR_variant	Exon 6 of 6	1		ENSP00000358434.5	Q9UGM6-2
WARS2	ENST00000495746.5 link	n.*241A>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

152268

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.000632

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000243

AC:

AN:

251486

Hom.:

AF XY:

0.000287

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000475

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000516

AC:

755

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000499

AC XY:

363

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000650

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000322

AC:

AN:

152386

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.000120

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:

0.000632

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000490

Hom.:

Bravo

AF:

0.000336

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 313 of the WARS2 protein (p.Lys313Met). This variant is present in population databases (rs145867327, gnomAD 0.05%). This missense change has been observed in individuals with WARS2-related leukoencephalopathy (PMID: 28650581, 28905505, 29783990, 30920170, 31282308). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 440917). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt WARS2 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Jan 23, 2018

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

WARS2-related disorder

Pathogenic:3

Jul 27, 2023

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.938A>T (p.Lys313Met) results in a non-conservative amino acid change in 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 0.00024 in 251486 control chromosomes (gnomAD). c.938A>T has been reported in the literature as a compound heterozygous genotype in multiple extensively genotyped individuals affected with WARS2-Related Disorders, primarily presenting with a combination of leukoencephalopathy, developmental delay, abnormal movements and lactic acidosis, and it has been found to segregate with the disorder in an autosomal recessive inheritance pattern within families (e.g. Theisen_2017, Wortmann_2017, Vantroys_2018, Maffezzini_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 30920170, 28650581, 29783990, 28905505). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 01, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as a compound heterozygous change in individuals with WARS2-related disorders (PMID: 28650581, 28905505, 30920170, 31282308, 35074316). Functional studies of patient fibroblasts and cells as well as expression in a yeast model provide evidence this variant impacts proper functioning of the protein (PMID: 28650581, 28905505, 30920170). The c.938A>T (p.Lys313Met) variant affects a moderately conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. The c.938A>T (p.Lys313Met) variant is present in the heterozygous state in the gnomAD V4 population database at a frequency of 0.05% (804/1614272) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.938A>T (p.Lys313Met) variant is classified as Pathogenic. -

Jun 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The WARS2 c.938A>T variant is predicted to result in the amino acid substitution p.Lys313Met. This variant was previously reported in the compound heterozygous state in multiple individuals who presented with neonatal or infantile-onset mitochondrial encephalopathy (Theisen et al. 2017. PubMed ID: 28650581; Wortmann et al. 2017. PubMed ID: 28905505; Vantroys et al. 2018. PubMed ID: 29783990). This variant is reported in 0.047% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

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

Pathogenic:2

Feb 17, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in WARS2 is predicted to replace lysine with methionine at codon 313, p.(Lys313Met). The lysine residue is highly conserved (100 vertebrates, UCSC), and is located in an helical region. There is a moderate physicochemical difference between lysine and methionine. The highest population minor allele frequency in gnomAD v2.1 is 0.05% (61/129,200 alleles) in the European (non-Finnish) population, which is conistent with a recessive condition. This variant has been detected in at least six individuals with early onset complex neurodevelopmental disorders. Of those individuals, three individuals were compound heterozygous for the variant and a likely pathogenic variant and one of those were confirmed in trans by parental testing (PMID: 28650581, 28905505, 29783990, 30920170, 31282308). The variant has been reported to segregate with disease in at least two families (PMID: 28905505, 30920170). At least three patient's with this variant displayed oxidative phophorylation complex analyses conistent with a defect in mitochondrial gene expression in patient cells (PMID: 28650581, 29783990, 30920170). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/6 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_Strong, PP1_Moderate, PM2_Supporting, PP4. -

Inborn genetic diseases

Uncertain:1

Dec 26, 2014

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

M_CAP

Benign

0.017

MetaRNN

Benign

0.22

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.18

Sift

Benign

0.21

Sift4G

Benign

0.12

Polyphen

0.71

Vest4

0.43

MVP

0.26

MPC

1.3

ClinPred

0.47

GERP RS

6.0

Varity_R

0.43

gMVP

0.58

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