chr1-150487873-C-T

Variant names:

• chr1-150487873-C-T
• rs1669218203
• NM_025150.5:c.82C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025150.5(TARS2):​c.82C>T​(p.Pro28Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TARS2 NM_025150.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.42

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13655815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TARS2	NM_025150.5	c.82C>T	p.Pro28Ser	missense_variant	Exon 2 of 18	ENST00000369064.8	NP_079426.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TARS2	ENST00000369064.8	c.82C>T	p.Pro28Ser	missense_variant	Exon 2 of 18	1	NM_025150.5	ENSP00000358060.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460706 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726662

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 16, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	.;T;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.6	N;N;.
REVEL	Benign	0.092
Sift	Benign	0.033	D;T;.
Sift4G	Benign	0.35	T;T;T
Polyphen		0.80	.;P;.
Vest4		0.13
MutPred		0.39		Gain of MoRF binding (P = 0.0477);Gain of MoRF binding (P = 0.0477);Gain of MoRF binding (P = 0.0477);
MVP		0.37
MPC		0.44
ClinPred		0.50	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.066
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1669218203; hg19: chr1-150460349;