chr1-150487873-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 14/21 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
• Publications: 0 publications found

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]

TARS2 Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation defect type 21

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025150.5. 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
	TARS2	NM_025150.5	MANE Select	c.82C>T	p.Pro28Ser	missense	Exon 2 of 18	NP_079426.2
	TARS2	NM_001271895.2		c.82C>T	p.Pro28Ser	missense	Exon 2 of 16	NP_001258824.1	U3KQG0
	TARS2	NM_001271896.2		c.82C>T	p.Pro28Ser	missense	Exon 2 of 14	NP_001258825.1	Q9BW92-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TARS2	ENST00000369064.8	TSL:1 MANE Select	c.82C>T	p.Pro28Ser	missense	Exon 2 of 18	ENSP00000358060.3	Q9BW92-1
	TARS2	ENST00000606933.5	TSL:1	c.82C>T	p.Pro28Ser	missense	Exon 2 of 16	ENSP00000475847.1	U3KQG0
	TARS2	ENST00000895426.1		c.82C>T	p.Pro28Ser	missense	Exon 2 of 17	ENSP00000565485.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4954

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111890

Other (OTH) AF: 0.00 AC: 0 AN: 60290

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.4
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.092
Sift	Benign	0.033	D
Sift4G	Benign	0.35	T
Polyphen		0.80	P
Vest4		0.13
MutPred		0.39		Gain of MoRF binding (P = 0.0477)
MVP		0.37
MPC		0.44
ClinPred		0.50	D
GERP RS		4.0
PromoterAI		0.048	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.066
gMVP		0.69
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs1669218203; hg19: chr1-150460349;