1-119033195-C-G

Variant names:

• chr1-119033195-C-G
• rs3790549
• NM_015836.4:c.799G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015836.4(WARS2):​c.799G>C​(p.Ala267Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0494 in 1,614,182 control chromosomes in the GnomAD database, including 2,726 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (453 hom., cov: 33)
  • Exomes 𝑓: 0.048 (2273 hom.)
• Consequence: WARS2 NM_015836.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.37
• Publications: 19 publications found

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]

WARS2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020585656).
• BP6: Variant 1-119033195-C-G is Benign according to our data. Variant chr1-119033195-C-G is described in ClinVar as Benign. ClinVar VariationId is 1169497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015836.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WARS2	NM_015836.4	MANE Select	c.799G>C	p.Ala267Pro	missense	Exon 6 of 6	NP_056651.1
	WARS2	NM_001378226.1		c.730G>C	p.Ala244Pro	missense	Exon 7 of 7	NP_001365155.1
	WARS2	NM_001378227.1		c.730G>C	p.Ala244Pro	missense	Exon 8 of 8	NP_001365156.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WARS2	ENST00000235521.5	TSL:1 MANE Select	c.799G>C	p.Ala267Pro	missense	Exon 6 of 6	ENSP00000235521.4
	WARS2	ENST00000369426.9	TSL:1	c.*165G>C		3_prime_UTR	Exon 6 of 6	ENSP00000358434.5
	WARS2	ENST00000495746.5	TSL:2	n.*102G>C		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.0661 AC: 10054 AN: 152212 Hom.: 447 Cov.: 33

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0529

Gnomad ASJ AF: 0.0395

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.0610

Gnomad FIN AF: 0.0301

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0446

Gnomad OTH AF: 0.0635

GnomAD2 exomes AF: 0.0571 AC: 14338 AN: 250910 AF XY: 0.0554

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.0311

Gnomad ASJ exome AF: 0.0364

Gnomad EAS exome AF: 0.188

Gnomad FIN exome AF: 0.0347

Gnomad NFE exome AF: 0.0445

Gnomad OTH exome AF: 0.0502

GnomAD4 exome AF: 0.0477 AC: 69684 AN: 1461852 Hom.: 2273 Cov.: 31 AF XY: 0.0478 AC XY: 34766 AN XY: 727232

African (AFR) AF: 0.107 AC: 3572 AN: 33480

American (AMR) AF: 0.0332 AC: 1483 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0373 AC: 974 AN: 26136

East Asian (EAS) AF: 0.178 AC: 7079 AN: 39700

South Asian (SAS) AF: 0.0560 AC: 4831 AN: 86256

European-Finnish (FIN) AF: 0.0354 AC: 1891 AN: 53384

Middle Eastern (MID) AF: 0.0674 AC: 389 AN: 5768

European-Non Finnish (NFE) AF: 0.0413 AC: 45967 AN: 1112010

Other (OTH) AF: 0.0579 AC: 3498 AN: 60394

GnomAD4 genome AF: 0.0661 AC: 10072 AN: 152330 Hom.: 453 Cov.: 33 AF XY: 0.0649 AC XY: 4831 AN XY: 74486

African (AFR) AF: 0.102 AC: 4243 AN: 41568

American (AMR) AF: 0.0529 AC: 809 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0395 AC: 137 AN: 3472

East Asian (EAS) AF: 0.196 AC: 1017 AN: 5178

South Asian (SAS) AF: 0.0608 AC: 294 AN: 4832

European-Finnish (FIN) AF: 0.0301 AC: 320 AN: 10624

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0446 AC: 3034 AN: 68028

Other (OTH) AF: 0.0718 AC: 152 AN: 2116

Alfa AF: 0.0507 Hom.: 187

Bravo AF: 0.0674

TwinsUK AF: 0.0440 AC: 163

ALSPAC AF: 0.0397 AC: 153

ESP6500AA AF: 0.103 AC: 454

ESP6500EA AF: 0.0431 AC: 371

ExAC AF: 0.0568 AC: 6901

Asia WGS AF: 0.145 AC: 505 AN: 3478

EpiCase AF: 0.0469

EpiControl AF: 0.0452

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.57	N
PhyloP100		2.4
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.096
Sift	Benign	0.15	T
Sift4G	Benign	0.14	T
Polyphen		0.51	P
Vest4		0.080
MPC		1.0
ClinPred		0.023	T
GERP RS		4.9
Varity_R		0.64
gMVP		0.55
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3790549; hg19: chr1-119575818; COSMIC: COSV52475819; COSMIC: COSV52475819;