rs145867327

chr1-119033056-T-Achr1-119033056-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• 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]

ACMG classification

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: {Pathogenic=2, Uncertain_significance=1, 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	UniProt
WARS2	NM_015836.4	c.938A>T	p.Lys313Met	missense_variant	6/6	ENST00000235521.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WARS2	ENST00000235521.5	c.938A>T	p.Lys313Met	missense_variant	6/6	1	NM_015836.4	P1
WARS2	ENST00000369426.9	c.*304A>T		3_prime_UTR_variant	6/6	1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152268 Hom.: 0 Cov.: 33

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: 61 AN: 251486 Hom.: 0 AF XY: 0.000287 AC XY: 39 AN XY: 135918

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.: 0 Cov.: 30 AF XY: 0.000499 AC XY: 363 AN XY: 727248

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: 49 AN: 152386 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74518

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.: 0

Bravo AF: 0.000336

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000818

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -
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	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

WARS2-related disorder Pathogenic:2

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.18
Sift	Benign	0.21	T
Sift4G	Benign	0.12	T
Polyphen		0.71	P
Vest4		0.43
MVP		0.26
MPC		1.3
ClinPred		0.47	T
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

Other links and lift over

dbSNP: rs145867327; hg19: chr1-119575679;