5-33453263-CTTTTTTTTTTTT-CTTTTTTTTT

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

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
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Variant has high frequency in the SAS (0.0356) population. However there is too low homozygotes in high coverage region: (expected more than 81, got 0).
• 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 VariationId is 3059544.Status of the report is no_assertion_criteria_provided, 0 stars.

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.330-6_330-4delTTT		splice_region intron	N/A	NP_689508.3
	TARS1	NM_001258438.2		c.429-6_429-4delTTT		splice_region intron	N/A	NP_001245367.1	P26639-2
	TARS1	NM_001258437.1		c.330-6_330-4delTTT		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.330-25_330-23delTTT		intron	N/A	ENSP00000265112.3	P26639-1
	TARS1	ENST00000509731.5	TSL:1	n.*283-25_*283-23delTTT		intron	N/A	ENSP00000427304.1	D6RJ97
	TARS1	ENST00000455217.6	TSL:2	c.429-25_429-23delTTT		intron	N/A	ENSP00000387710.2	P26639-2

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

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

African (AFR) AF: 0.0234 AC: 610 AN: 26070

American (AMR) AF: 0.0338 AC: 681 AN: 20152

Ashkenazi Jewish (ASJ) AF: 0.0247 AC: 466 AN: 18860

East Asian (EAS) AF: 0.0215 AC: 668 AN: 31116

South Asian (SAS) AF: 0.0370 AC: 1949 AN: 52722

European-Finnish (FIN) AF: 0.0319 AC: 1082 AN: 33898

Middle Eastern (MID) AF: 0.0197 AC: 84 AN: 4260

European-Non Finnish (NFE) AF: 0.0146 AC: 14045 AN: 963512

Other (OTH) AF: 0.0215 AC: 1052 AN: 48934

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

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

African (AFR) AF: 0.0000672 AC: 2 AN: 29764

American (AMR) AF: 0.00 AC: 0 AN: 9526

Ashkenazi Jewish (ASJ) AF: 0.000377 AC: 1 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 2674

South Asian (SAS) AF: 0.00 AC: 0 AN: 2934

European-Finnish (FIN) AF: 0.000222 AC: 1 AN: 4508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 182

European-Non Finnish (NFE) AF: 0.0000787 AC: 4 AN: 50844

Other (OTH) AF: 0.00 AC: 0 AN: 1392

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00324779), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 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)		0.020		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: COSV54311456; COSMIC: COSV54311456;