rs145867327
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4
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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00032 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00052 ( 0 hom. )
Consequence
WARS2
NM_015836.4 missense
NM_015836.4 missense
Scores
5
14
Clinical Significance
Conservation
PhyloP100: 3.08
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 440917.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, Likely_pathogenic=3}. 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.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| WARS2 | NM_015836.4 | c.938A>T | p.Lys313Met | missense_variant | 6/6 | ENST00000235521.5 | NP_056651.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| WARS2 | ENST00000235521.5 | c.938A>T | p.Lys313Met | missense_variant | 6/6 | 1 | NM_015836.4 | ENSP00000235521.4 | ||
| WARS2 | ENST00000369426 | c.*304A>T | 3_prime_UTR_variant | 6/6 | 1 | ENSP00000358434.5 |
Frequencies
GnomAD3 genomes 0.000322 AC: 49AN: 152268Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000243 AC: 61AN: 251486Hom.: 0 AF XY: 0.000287 AC XY: 39AN XY: 135918
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GnomAD4 exome AF: 0.000516 AC: 755AN: 1461886Hom.: 0 Cov.: 30 AF XY: 0.000499 AC XY: 363AN XY: 727248
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GnomAD4 genome 0.000322 AC: 49AN: 152386Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26AN XY: 74518
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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
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 17, 2023 | 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 23, 2018 | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
WARS2-related disorder Pathogenic:3
| Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 20, 2024 | 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant has been previously reported as a compound heterozygous change in patients with WARS2 -related disorders (PMID: 28650581, 28905505, 30920170, 31282308, 35074316). Functional studies showed that the c.938A>T (p.Lys313Met) variant alters the function of the WARS2 protein (PMID: 28650581, 28905505, 30920170). The c.938A>T (p.Lys313Met) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.024% (69/282894) and is absent in the homozygous state, thus is presumed to be rare. 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. Based on the available evidence, the c.938A>T (p.Lys313Met) variant is classified as Likely Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 27, 2023 | 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. - |
Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures Pathogenic:2
| Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 17, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Mar 30, 2023 | 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
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 26, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
P
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at