rs1057990

Variant names:

• chr1-119032609-T-A
• rs1057990
• NM_015836.4:c.*302A>T

Your query was ambiguous. Multiple possible variants found:

• chr1-119032609-T-A
• chr1-119032609-T-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015836.4(WARS2):​c.*302A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000457 in 218,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: WARS2 NM_015836.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.202
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WARS2	NM_015836.4	c.*302A>T		3_prime_UTR_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.*302A>T		3_prime_UTR_variant	Exon 6 of 6	1	NM_015836.4	ENSP00000235521.4
WARS2	ENST00000369426.9	c.*751A>T		3_prime_UTR_variant	Exon 6 of 6	1		ENSP00000358434.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000457 AC: 1 AN: 218908 Hom.: 0 Cov.: 0 AF XY: 0.00000878 AC XY: 1 AN XY: 113952

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 6490

American (AMR) AF: 0.00 AC: 0 AN: 7262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6908

East Asian (EAS) AF: 0.00 AC: 0 AN: 12736

South Asian (SAS) AF: 0.00 AC: 0 AN: 22330

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 996

European-Non Finnish (NFE) AF: 0.00000730 AC: 1 AN: 137062

Other (OTH) AF: 0.00 AC: 0 AN: 12860

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.4
DANN	Benign	0.81
PhyloP100		-0.20

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: rs1057990; hg19: chr1-119575232;