rs1253426801

Variant names:

• chr1-119076372-CT-C
• rs1253426801
• NM_015836.4:c.325delA

Your query was ambiguous. Multiple possible variants found:

• chr1-119076372-CT-C
• chr1-119076372-CT-CTT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_015836.4(WARS2):​c.325delA​(p.Ser109AlafsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WARS2 NM_015836.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 1.88
• Publications: 3 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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.325delA	p.Ser109AlafsTer15	frameshift	Exon 2 of 6	NP_056651.1	Q9UGM6-1
	WARS2	NM_001378226.1		c.256delA	p.Ser86AlafsTer15	frameshift	Exon 3 of 7	NP_001365155.1
	WARS2	NM_001378227.1		c.256delA	p.Ser86AlafsTer15	frameshift	Exon 4 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.325delA	p.Ser109AlafsTer15	frameshift	Exon 2 of 6	ENSP00000235521.4	Q9UGM6-1
	WARS2	ENST00000369426.9	TSL:1	c.325delA	p.Ser109AlafsTer15	frameshift	Exon 2 of 6	ENSP00000358434.5	Q9UGM6-2
	WARS2	ENST00000928547.1		c.325delA	p.Ser109AlafsTer15	frameshift	Exon 2 of 7	ENSP00000598606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250632 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs1253426801; hg19: chr1-119618995; COSMIC: COSV52483099;