5-33453263-CTTTTTTTTTTTT-CTTTTTTTTTTT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_152295.5(TARS1):​c.330-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 105,184 control chromosomes in the GnomAD database, including 1,223 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 0.18 (1223 hom., cov: 22)
  • Exomes 𝑓: 0.30 (124 hom.)
  • Failed GnomAD Quality Control
• Consequence: TARS1 NM_152295.5 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.694
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• trichothiodystrophy 7, nonphotosensitive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, G2P
• trichothiodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 5-33453263-CT-C is Benign according to our data. Variant chr5-33453263-CT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3060916.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152295.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TARS1	NM_152295.5	MANE Select	c.330-4delT		splice_region intron	N/A	NP_689508.3
	TARS1	NM_001258438.2		c.429-4delT		splice_region intron	N/A	NP_001245367.1	P26639-2
	TARS1	NM_001258437.1		c.330-4delT		splice_region intron	N/A	NP_001245366.1	P26639-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TARS1	ENST00000265112.8	TSL:1 MANE Select	c.330-25delT		intron	N/A	ENSP00000265112.3	P26639-1
	TARS1	ENST00000509731.5	TSL:1	n.*283-25delT		intron	N/A	ENSP00000427304.1	D6RJ97
	TARS1	ENST00000455217.6	TSL:2	c.429-25delT		intron	N/A	ENSP00000387710.2	P26639-2

Frequencies

GnomAD3 genomes AF: 0.180 AC: 18920 AN: 105182 Hom.: 1221 Cov.: 22

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.0456

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.148

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.164

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.304 AC: 358596 AN: 1178478 Hom.: 124 Cov.: 0 AF XY: 0.299 AC XY: 173477 AN XY: 579342

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.303 AC: 7882 AN: 26010

American (AMR) AF: 0.185 AC: 3793 AN: 20550

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 4895 AN: 18970

East Asian (EAS) AF: 0.250 AC: 7808 AN: 31292

South Asian (SAS) AF: 0.224 AC: 11920 AN: 53274

European-Finnish (FIN) AF: 0.216 AC: 7451 AN: 34560

Middle Eastern (MID) AF: 0.300 AC: 1272 AN: 4246

European-Non Finnish (NFE) AF: 0.318 AC: 299239 AN: 941278

Other (OTH) AF: 0.297 AC: 14336 AN: 48298

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.180 AC: 18909 AN: 105184 Hom.: 1223 Cov.: 22 AF XY: 0.179 AC XY: 8877 AN XY: 49628

African (AFR) AF: 0.203 AC: 6061 AN: 29796

American (AMR) AF: 0.146 AC: 1393 AN: 9530

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 293 AN: 2652

East Asian (EAS) AF: 0.0454 AC: 121 AN: 2666

South Asian (SAS) AF: 0.307 AC: 894 AN: 2916

European-Finnish (FIN) AF: 0.166 AC: 748 AN: 4506

Middle Eastern (MID) AF: 0.141 AC: 24 AN: 170

European-Non Finnish (NFE) AF: 0.178 AC: 9047 AN: 50822

Other (OTH) AF: 0.166 AC: 232 AN: 1396

Alfa AF: 0.0373 Hom.: 62

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	TARS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.69
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35931457; hg19: chr5-33453368; COSMIC: COSV54309712; COSMIC: COSV54309712;