NM_015836.4:c.46A>T

Variant names:

• chr1-119140599-T-A
• NM_015836.4:c.46A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_015836.4(WARS2):​c.46A>T​(p.Ile16Phe) variant causes a missense 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I16M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: WARS2 NM_015836.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.23
• 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-AS1 (HGNC:40612): (WARS2 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_015836.4
• 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.46A>T	p.Ile16Phe	missense	Exon 1 of 6	NP_056651.1	Q9UGM6-1
	WARS2	NM_001378228.1		c.46A>T	p.Ile16Phe	missense	Exon 1 of 6	NP_001365157.1	B7Z6G7
	WARS2	NM_001378229.1		c.46A>T	p.Ile16Phe	missense	Exon 1 of 5	NP_001365158.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WARS2	ENST00000235521.5	TSL:1 MANE Select	c.46A>T	p.Ile16Phe	missense	Exon 1 of 6	ENSP00000235521.4	Q9UGM6-1
	WARS2	ENST00000369426.9	TSL:1	c.46A>T	p.Ile16Phe	missense	Exon 1 of 6	ENSP00000358434.5	Q9UGM6-2
	WARS2-AS1	ENST00000425884.7	TSL:1	n.204T>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.061	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0084	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.25	N
REVEL	Benign	0.15
Sift	Uncertain	0.016	D
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.72
MutPred		0.37		Gain of disorder (P = 0.0836)
MVP		0.25
MPC		0.74
ClinPred		0.93	D
GERP RS		4.9
PromoterAI		0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.62
Mutation Taster		=81/19	polymorphism

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

hg19: chr1-119683222;