5-33453263-CTTT-C

Variant names:

• chr5-33453263-CTTT-C
• rs35931457
• NM_152295.5:c.330-6_330-4delTTT

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP6 BS1

The NM_152295.5(TARS1):​c.330-6_330-4delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,304,732 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000076 (0 hom., cov: 22)
  • Exomes 𝑓: 0.017 (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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 5-33453263-CTTT-C is Benign according to our data. Variant chr5-33453263-CTTT-C is described in ClinVar as [Likely_benign]. Clinvar id is 3059544.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 = 0.0172 (20637/1199524) while in subpopulation SAS AF= 0.037 (1949/52722). AF 95% confidence interval is 0.0356. There are 0 homozygotes in gnomad4_exome. There are 10838 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TARS1	NM_152295.5	c.330-6_330-4delTTT		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.330-25_330-23delTTT		intron_variant	Intron 3 of 18	1	NM_152295.5	ENSP00000265112.3

Frequencies

GnomAD3 genomes AF: 0.0000760 AC: 8 AN: 105208 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000672

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000222

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000787

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0172 AC: 20637 AN: 1199524 Hom.: 0 AF XY: 0.0184 AC XY: 10838 AN XY: 588488

Gnomad4 AFR exome AF: 0.0234

Gnomad4 AMR exome AF: 0.0338

Gnomad4 ASJ exome AF: 0.0247

Gnomad4 EAS exome AF: 0.0215

Gnomad4 SAS exome AF: 0.0370

Gnomad4 FIN exome AF: 0.0319

Gnomad4 NFE exome AF: 0.0146

Gnomad4 OTH exome AF: 0.0215

GnomAD4 genome AF: 0.0000760 AC: 8 AN: 105208 Hom.: 0 Cov.: 22 AF XY: 0.0000806 AC XY: 4 AN XY: 49624

Gnomad4 AFR AF: 0.0000672

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000377

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000222

Gnomad4 NFE AF: 0.0000787

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TARS1-related disorder Benign:1

Nov 12, 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)		0.020		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;