5-33453263-CTTTTTTTTTTTT-CTTTTTTTTTTTTT

Variant names:

• chr5-33453263-C-CT
• rs35931457
• NM_152295.5:c.330-4dupT

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_152295.5(TARS1):​c.330-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 1,323,796 control chromosomes in the GnomAD database, including 7 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0066 (7 hom., cov: 22)
  • Exomes 𝑓: 0.024 (0 hom.)
• Consequence: TARS1 NM_152295.5 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.694

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 -9 ACMG points.

• BP6: Variant 5-33453263-C-CT is Benign according to our data. Variant chr5-33453263-C-CT is described in ClinVar as [Likely_benign]. Clinvar id is 3037640.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0244 (29686/1218620) while in subpopulation SAS AF= 0.0289 (1564/54206). AF 95% confidence interval is 0.0277. There are 0 homozygotes in gnomad4_exome. There are 14316 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TARS1	NM_152295.5	c.330-4dupT		splice_region_variant, intron_variant	Intron 3 of 18	ENST00000265112.8	NP_689508.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TARS1	ENST00000265112.8	c.330-26_330-25insT		intron_variant	Intron 3 of 18	1	NM_152295.5	ENSP00000265112.3

Frequencies

GnomAD3 genomes AF: 0.00662 AC: 696 AN: 105172 Hom.: 7 Cov.: 22

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00441

Gnomad ASJ AF: 0.00452

Gnomad EAS AF: 0.00859

Gnomad SAS AF: 0.00716

Gnomad FIN AF: 0.00200

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00527

Gnomad OTH AF: 0.00288

GnomAD4 exome AF: 0.0244 AC: 29686 AN: 1218620 Hom.: 0 Cov.: 0 AF XY: 0.0239 AC XY: 14316 AN XY: 598602

Gnomad4 AFR exome AF: 0.0242

Gnomad4 AMR exome AF: 0.0205

Gnomad4 ASJ exome AF: 0.0262

Gnomad4 EAS exome AF: 0.0199

Gnomad4 SAS exome AF: 0.0289

Gnomad4 FIN exome AF: 0.0203

Gnomad4 NFE exome AF: 0.0246

Gnomad4 OTH exome AF: 0.0228

GnomAD4 genome AF: 0.00661 AC: 695 AN: 105176 Hom.: 7 Cov.: 22 AF XY: 0.00604 AC XY: 300 AN XY: 49632

Gnomad4 AFR AF: 0.0106

Gnomad4 AMR AF: 0.00441

Gnomad4 ASJ AF: 0.00452

Gnomad4 EAS AF: 0.00863

Gnomad4 SAS AF: 0.00721

Gnomad4 FIN AF: 0.00200

Gnomad4 NFE AF: 0.00527

Gnomad4 OTH AF: 0.00287

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TARS1-related disorder Benign:1

Nov 25, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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

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: rs35931457; hg19: chr5-33453368;