rs11541416

chr5-33453311-G-Achr5-33453311-G-T

Variant summary

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

The NM_152295.5(TARS1):c.352G>A(p.Val118Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00107 in 1,546,276 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (8 hom., cov: 29)
  • Exomes 𝑓: 0.00059 (8 hom.)
• Consequence: TARS1 NM_152295.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.85

Genes affected

TARS1 (HGNC:11572): (threonyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Threonyl-tRNA synthetase belongs to the class-II aminoacyl-tRNA synthetase family [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006256461).
• BP6: Variant 5-33453311-G-A is Benign according to our data. Variant chr5-33453311-G-A is described in ClinVar as [Benign]. Clinvar id is 716827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00614 (825/134256) while in subpopulation AFR AF= 0.0219 (776/35384). AF 95% confidence interval is 0.0207. There are 8 homozygotes in gnomad4. There are 362 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TARS1	NM_152295.5	c.352G>A	p.Val118Ile	missense_variant	4/19	ENST00000265112.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TARS1	ENST00000265112.8	c.352G>A	p.Val118Ile	missense_variant	4/19	1	NM_152295.5	P1

Frequencies

GnomAD3 genomes AF: 0.00610 AC: 818 AN: 134198 Hom.: 8 Cov.: 29

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00293

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000438

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000766

Gnomad OTH AF: 0.00394

GnomAD3 exomes AF: 0.00152 AC: 366 AN: 240640 Hom.: 2 AF XY: 0.00104 AC XY: 136 AN XY: 130540

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000175

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000119

Gnomad OTH exome AF: 0.000864

GnomAD4 exome AF: 0.000591 AC: 834 AN: 1412020 Hom.: 8 Cov.: 38 AF XY: 0.000535 AC XY: 375 AN XY: 701528

Gnomad4 AFR exome AF: 0.0201

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000161

Gnomad4 SAS exome AF: 0.0000374

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000435

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.00614 AC: 825 AN: 134256 Hom.: 8 Cov.: 29 AF XY: 0.00569 AC XY: 362 AN XY: 63624

Gnomad4 AFR AF: 0.0219

Gnomad4 AMR AF: 0.00293

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000439

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000766

Gnomad4 OTH AF: 0.00393

Alfa AF: 0.0246 Hom.: 2354

Bravo AF: 0.00666

ESP6500AA AF: 0.0200 AC: 88

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00171 AC: 208

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2018

- -

TARS1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 13, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	20
Dann	Benign	0.97
DEOGEN2	Benign	0.0086	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.10
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0063	T
MutationTaster	Benign	1.0	D;D;D;D;D
Sift4G	Benign	0.087	T
Vest4		0.39
MVP		0.53
ClinPred		0.051	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11541416; hg19: chr5-33453416;