1-119032674-C-T

Variant names:

• chr1-119032674-C-T
• rs3790548
• NM_015836.4:c.*237G>A

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.*237G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000367 in 517,988 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: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: WARS2 NM_015836.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.69
• Publications: 2 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=-0.85).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WARS2	NM_015836.4	MANE Select	c.*237G>A		3_prime_UTR	Exon 6 of 6	NP_056651.1	Q9UGM6-1
	WARS2	NM_001378226.1		c.*237G>A		3_prime_UTR	Exon 7 of 7	NP_001365155.1
	WARS2	NM_001378227.1		c.*237G>A		3_prime_UTR	Exon 8 of 8	NP_001365156.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WARS2	ENST00000235521.5	TSL:1 MANE Select	c.*237G>A		3_prime_UTR	Exon 6 of 6	ENSP00000235521.4	Q9UGM6-1
	WARS2	ENST00000369426.9	TSL:1	c.*686G>A		3_prime_UTR	Exon 6 of 6	ENSP00000358434.5	Q9UGM6-2
	WARS2	ENST00000928547.1		c.*237G>A		3_prime_UTR	Exon 7 of 7	ENSP00000598606.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000410 AC: 15 AN: 365832 Hom.: 0 Cov.: 4 AF XY: 0.0000471 AC XY: 9 AN XY: 190980

African (AFR) AF: 0.00 AC: 0 AN: 10452

American (AMR) AF: 0.00 AC: 0 AN: 11812

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11578

East Asian (EAS) AF: 0.00 AC: 0 AN: 24870

South Asian (SAS) AF: 0.00 AC: 0 AN: 32654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23758

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1666

European-Non Finnish (NFE) AF: 0.0000616 AC: 14 AN: 227418

Other (OTH) AF: 0.0000462 AC: 1 AN: 21624

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41412

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 13

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.42
DANN	Benign	0.76
PhyloP100		-1.7

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: rs3790548; hg19: chr1-119575297;