chr1-150497543-A-G

Position:

• chr1-150497543-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000369064.8(TARS2):​c.1034A>G​(p.His345Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00666 in 1,614,066 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H345H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0054 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (49 hom.)
• Consequence: TARS2 ENST00000369064.8 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0130

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004318863).
• BP6: Variant 1-150497543-A-G is Benign according to our data. Variant chr1-150497543-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 380192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00535 (815/152288) while in subpopulation NFE AF= 0.00723 (492/68014). AF 95% confidence interval is 0.00671. There are 6 homozygotes in gnomad4. There are 410 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TARS2	NM_025150.5	c.1034A>G	p.His345Arg	missense_variant	10/18	ENST00000369064.8	NP_079426.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TARS2	ENST00000369064.8	c.1034A>G	p.His345Arg	missense_variant	10/18	1	NM_025150.5	ENSP00000358060	P1

Frequencies

GnomAD3 genomes AF: 0.00536 AC: 815 AN: 152170 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00723

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00496 AC: 1245 AN: 251124 Hom.: 4 AF XY: 0.00481 AC XY: 653 AN XY: 135784

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00193

Gnomad FIN exome AF: 0.0108

Gnomad NFE exome AF: 0.00722

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.00679 AC: 9932 AN: 1461778 Hom.: 49 Cov.: 31 AF XY: 0.00662 AC XY: 4812 AN XY: 727198

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00197

Gnomad4 FIN exome AF: 0.0101

Gnomad4 NFE exome AF: 0.00779

Gnomad4 OTH exome AF: 0.00631

GnomAD4 genome AF: 0.00535 AC: 815 AN: 152288 Hom.: 6 Cov.: 32 AF XY: 0.00551 AC XY: 410 AN XY: 74464

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0101

Gnomad4 NFE AF: 0.00723

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00638 Hom.: 4

Bravo AF: 0.00531

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00884 AC: 76

ExAC AF: 0.00509 AC: 618

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00605

EpiControl AF: 0.00693

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 2019	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 14, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 19, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	TARS2: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.75
DANN	Benign	0.25
DEOGEN2	Benign	0.0032	T;.;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.60	T;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0043	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-2.4	.;.;N;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	2.5	.;N;N;.
REVEL	Benign	0.067
Sift	Benign	0.47	.;T;T;.
Sift4G	Benign	0.69	T;T;T;T
Polyphen		0.0	.;.;B;.
Vest4		0.19
MVP		0.37
MPC		0.52
ClinPred		0.0035	T
GERP RS		0.48
Varity_R		0.018
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs115390773; hg19: chr1-150470019;