1-119033045-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015836.4(WARS2):c.949A>G(p.Ile317Val) variant causes a missense change. The variant allele was found at a frequency of 0.000106 in 1,614,248 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: WARS2 NM_015836.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.90

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01042676).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WARS2	NM_015836.4	c.949A>G	p.Ile317Val	missense_variant	6/6	ENST00000235521.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WARS2	ENST00000235521.5	c.949A>G	p.Ile317Val	missense_variant	6/6	1	NM_015836.4	P1
WARS2	ENST00000369426.9	c.*315A>G		3_prime_UTR_variant	6/6	1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152238 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: 0.00173

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000151 AC: 38 AN: 251490 Hom.: 0 AF XY: 0.000162 AC XY: 22 AN XY: 135920

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00163

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000101 AC: 148 AN: 1461892 Hom.: 1 Cov.: 30 AF XY: 0.000110 AC XY: 80 AN XY: 727248

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00146

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152356 Hom.: 2 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74512

Gnomad4 AFR AF: 0.000264

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000606 Hom.: 0

Bravo AF: 0.000106

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000173 AC: 21

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2022

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 317 of the WARS2 protein (p.Ile317Val). This variant is present in population databases (rs75040541, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with WARS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1411807). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.13
Sift	Benign	0.059	T
Sift4G	Benign	0.14	T
Polyphen		0.47	P
Vest4		0.20
MVP		0.10
MPC		1.1
ClinPred		0.056	T
GERP RS		4.8
Varity_R		0.24
gMVP		0.36

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: rs75040541; hg19: chr1-119575668;