NM_015836.4:c.956G>T

Variant names:

• chr1-119033038-C-A
• rs376728283
• NM_015836.4:c.956G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015836.4(WARS2):​c.956G>T​(p.Arg319Leu) 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R319H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: WARS2 NM_015836.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.143

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054967433).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WARS2	NM_015836.4	c.956G>T	p.Arg319Leu	missense_variant	Exon 6 of 6	ENST00000235521.5	NP_056651.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WARS2	ENST00000235521.5	c.956G>T	p.Arg319Leu	missense_variant	Exon 6 of 6	1	NM_015836.4	ENSP00000235521.4
WARS2	ENST00000369426	c.*322G>T		3_prime_UTR_variant	Exon 6 of 6	1		ENSP00000358434.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251486 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135920

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.94	L
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.077
Sift	Benign	0.13	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.43		Loss of methylation at K318 (P = 0.0306);
MVP		0.082
MPC		0.55
ClinPred		0.21	T
GERP RS		-2.2
Varity_R		0.33
gMVP		0.28

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: rs376728283; hg19: chr1-119575661;