1-119033112-G-T

Position:

• chr1-119033112-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015836.4(WARS2):​c.882C>A​(p.Ser294Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S294S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: WARS2 NM_015836.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.976

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15442127).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WARS2	NM_015836.4	c.882C>A	p.Ser294Arg	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.882C>A	p.Ser294Arg	missense_variant	6/6	1	NM_015836.4	ENSP00000235521.4
WARS2	ENST00000369426	c.*248C>A		3_prime_UTR_variant	6/6	1		ENSP00000358434.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Parkinsonism-dystonia 3, childhood-onset Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

Dec 21, 2022

The c.882C>A variant is not present in publicly available population databases like 1000 Genomes, ExAC, EVS, Indian Exome Database, gnomAD or our in-house exome database. This variant has neither been published nor reported to clinical databases like ClinVar, HGMD and OMIM in any affected individuals. In silico pathogenicity prediction programs like SIFT, PolyPhen-2, CADD etc predicted this variant to be likely deleterious, however these predictions were not confirmed by any published functional studies. This patient harbours another heterozygous variant (c.37T>G) in WARS2 gene. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.8
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.10
Sift	Benign	0.33	T
Sift4G	Benign	0.35	T
Polyphen		0.55	P
Vest4		0.19
MutPred		0.53		Gain of methylation at S294 (P = 0.0175);
MVP		0.082
MPC		1.1
ClinPred		0.63	D
GERP RS		-0.94
Varity_R		0.77
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-119575735;