chr1-150487934-A-G

Position:

• chr1-150487934-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_025150.5(TARS2):​c.143A>G​(p.Lys48Arg) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TARS2 NM_025150.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28

Genes affected

TARS2 (HGNC:30740): (threonyl-tRNA synthetase 2, mitochondrial) This gene encodes a member of the class-II aminoacyl-tRNA synthetase family. The encoded protein is a mitochondrial aminoacyl-tRNA synthetase. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 4. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TARS2	NM_025150.5	c.143A>G	p.Lys48Arg	missense_variant	2/18	ENST00000369064.8	NP_079426.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TARS2	ENST00000369064.8	c.143A>G	p.Lys48Arg	missense_variant	2/18	1	NM_025150.5	ENSP00000358060	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 13, 2022

This variant has not been reported in the literature in individuals affected with TARS2-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 48 of the TARS2 protein (p.Lys48Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	.;T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.088	N
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.093	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.76	N;N;.
REVEL	Benign	0.057
Sift	Benign	0.77	T;T;.
Sift4G	Benign	0.26	T;T;T
Polyphen		0.56	.;P;.
Vest4		0.22
MutPred		0.38		Loss of ubiquitination at K48 (P = 0.0167);Loss of ubiquitination at K48 (P = 0.0167);Loss of ubiquitination at K48 (P = 0.0167);
MVP		0.39
MPC		0.43
ClinPred		0.30	T
GERP RS		4.0
Varity_R		0.079
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.57		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1669220997; hg19: chr1-150460410;