chr1-119033056-T-G

Variant names:

• chr1-119033056-T-G
• rs145867327
• NM_015836.4:c.938A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_015836.4(WARS2):​c.938A>C​(p.Lys313Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K313M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: WARS2 NM_015836.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.08
• Publications: 9 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-119033056-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 440917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20971787).

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.938A>C	p.Lys313Thr	missense	Exon 6 of 6	NP_056651.1
	WARS2	NM_001378226.1		c.869A>C	p.Lys290Thr	missense	Exon 7 of 7	NP_001365155.1
	WARS2	NM_001378227.1		c.869A>C	p.Lys290Thr	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.938A>C	p.Lys313Thr	missense	Exon 6 of 6	ENSP00000235521.4
	WARS2	ENST00000369426.9	TSL:1	c.*304A>C		3_prime_UTR	Exon 6 of 6	ENSP00000358434.5
	WARS2	ENST00000495746.5	TSL:2	n.*241A>C		downstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.071
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.1
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.11
Sift	Benign	0.47	T
Sift4G	Benign	0.54	T
Polyphen		0.030	B
Vest4		0.47
MutPred		0.40		Loss of methylation at K313 (P = 0.035)
MVP		0.29
MPC		0.87
ClinPred		0.93	D
GERP RS		6.0
Varity_R		0.44
gMVP		0.53
Mutation Taster		=29/71	disease causing

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: rs145867327; hg19: chr1-119575679;