5-33448633-A-C

Position:

• chr5-33448633-A-C

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.231A>C​(p.Glu77Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,613,966 control chromosomes in the GnomAD database, including 58 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (45 hom.)
• Consequence: TARS1 NM_152295.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.237

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]

TARS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023596287).
• BP6: Variant 5-33448633-A-C is Benign according to our data. Variant chr5-33448633-A-C is described in ClinVar as [Benign]. Clinvar id is 771370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00308 (469/152338) while in subpopulation AMR AF= 0.0275 (420/15296). AF 95% confidence interval is 0.0253. There are 13 homozygotes in gnomad4. There are 232 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TARS1	NM_152295.5	c.231A>C	p.Glu77Asp	missense_variant	3/19	ENST00000265112.8	NP_689508.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TARS1	ENST00000265112.8	c.231A>C	p.Glu77Asp	missense_variant	3/19	1	NM_152295.5	ENSP00000265112.3

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 466 AN: 152220 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0273

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00550 AC: 1382 AN: 251324 Hom.: 31 AF XY: 0.00420 AC XY: 571 AN XY: 135824

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.0379

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00135 AC: 1973 AN: 1461628 Hom.: 45 Cov.: 30 AF XY: 0.00122 AC XY: 886 AN XY: 727110

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.0387

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000303

Gnomad4 SAS exome AF: 0.000823

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000504

Gnomad4 OTH exome AF: 0.00147

GnomAD4 genome AF: 0.00308 AC: 469 AN: 152338 Hom.: 13 Cov.: 32 AF XY: 0.00311 AC XY: 232 AN XY: 74496

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.0275

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.000370 Hom.: 0

Bravo AF: 0.00556

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00441 AC: 536

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 08, 2018	- -

TARS1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 03, 2019

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	0.13
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T;.;T;.;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.50	D
LIST_S2	Uncertain	0.95	.;D;D;D;D
MetaRNN	Benign	0.0024	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.;N;N;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.29	N;N;N;N;N
REVEL	Benign	0.068
Sift	Benign	0.56	T;T;T;T;D
Sift4G	Benign	0.58	T;T;T;T;T
Polyphen		0.060	B;.;B;.;.
Vest4		0.22
MutPred		0.28		Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);.;
MVP		0.26
MPC		0.18
ClinPred		0.0090	T
GERP RS		0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.029
gMVP		0.34

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: rs146538659; hg19: chr5-33448739;