chr15-101685929-A-G

Position:

• chr15-101685929-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000335968.8(TARS3):​c.1454T>C​(p.Phe485Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TARS3 ENST00000335968.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.09

Genes affected

TARS3 (HGNC:24728): (threonyl-tRNA synthetase 3) Predicted to enable threonine-tRNA ligase activity. Predicted to be involved in threonyl-tRNA aminoacylation. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

TARS3 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TARS3	NM_152334.3	c.1454T>C	p.Phe485Ser	missense_variant	11/19	ENST00000335968.8	NP_689547.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TARS3	ENST00000335968.8	c.1454T>C	p.Phe485Ser	missense_variant	11/19	1	NM_152334.3	ENSP00000338093.3

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 specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2024

The c.1454T>C (p.F485S) alteration is located in exon 11 (coding exon 11) of the TARSL2 gene. This alteration results from a T to C substitution at nucleotide position 1454, causing the phenylalanine (F) at amino acid position 485 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.8	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-7.2	D;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0080	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.80		Loss of catalytic residue at F485 (P = 9e-04);Loss of catalytic residue at F485 (P = 9e-04);
MVP		0.93
MPC		0.19
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.81
gMVP		0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs1898454769; hg19: chr15-102226132;