5-33445328-G-A

Position:

• chr5-33445328-G-A

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.62G>A​(p.Gly21Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,611,470 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (27 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (23 hom.)
• Consequence: TARS1 NM_152295.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.199

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=0.0024833381).
• BP6: Variant 5-33445328-G-A is Benign according to our data. Variant chr5-33445328-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 782449.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 = 0.0104 (1584/152224) while in subpopulation AFR AF= 0.0364 (1510/41518). AF 95% confidence interval is 0.0348. There are 27 homozygotes in gnomad4. There are 740 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TARS1	NM_152295.5	c.62G>A	p.Gly21Asp	missense_variant	2/19	ENST00000265112.8	NP_689508.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TARS1	ENST00000265112.8	c.62G>A	p.Gly21Asp	missense_variant	2/19	1	NM_152295.5	ENSP00000265112.3

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1582 AN: 152106 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0364

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00253 AC: 627 AN: 247994 Hom.: 10 AF XY: 0.00177 AC XY: 237 AN XY: 134072

Gnomad AFR exome AF: 0.0360

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000662

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000977 AC: 1425 AN: 1459246 Hom.: 23 Cov.: 30 AF XY: 0.000816 AC XY: 592 AN XY: 725796

Gnomad4 AFR exome AF: 0.0358

Gnomad4 AMR exome AF: 0.00146

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000931

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00221

GnomAD4 genome AF: 0.0104 AC: 1584 AN: 152224 Hom.: 27 Cov.: 32 AF XY: 0.00994 AC XY: 740 AN XY: 74444

Gnomad4 AFR AF: 0.0364

Gnomad4 AMR AF: 0.00360

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00189 Hom.: 9

Bravo AF: 0.0116

ESP6500AA AF: 0.0340 AC: 150

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00326 AC: 396

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 18, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Trichothiodystrophy 7, nonphotosensitive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 17, 2022

- -

TARS1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 20, 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	0.090
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.97
DANN	Benign	0.74
DEOGEN2	Benign	0.011	T;.;T;.;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.58	.;T;T;T;T;T
MetaRNN	Benign	0.0025	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;L;L;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.030	N;N;N;N;.;.
REVEL	Benign	0.041
Sift	Benign	0.82	T;T;T;T;.;.
Sift4G	Benign	0.43	T;T;T;T;T;T
Polyphen		0.0	B;.;B;.;.;.
Vest4		0.26
MVP		0.13
MPC		0.25
ClinPred		0.0074	T
GERP RS		-0.41
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.084
gMVP		0.37

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: rs34334786; hg19: chr5-33445434;