5-33453263-CTTTTTTTTTTTT-CTTTT

Variant names:

• chr5-33453263-CTTTTTTTT-C
• rs35931457
• NM_152295.5:c.330-11_330-4delTTTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152295.5(TARS1):​c.330-11_330-4delTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000485 in 1,237,288 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TARS1 NM_152295.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.61
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.330-11_330-4delTTTTTTTT		splice_region intron	N/A	NP_689508.3
	TARS1	NM_001258438.2		c.429-11_429-4delTTTTTTTT		splice_region intron	N/A	NP_001245367.1	P26639-2
	TARS1	NM_001258437.1		c.330-11_330-4delTTTTTTTT		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_330-18delTTTTTTTT		intron	N/A	ENSP00000265112.3	P26639-1
	TARS1	ENST00000509731.5	TSL:1	n.*283-25_*283-18delTTTTTTTT		intron	N/A	ENSP00000427304.1	D6RJ97
	TARS1	ENST00000455217.6	TSL:2	c.429-25_429-18delTTTTTTTT		intron	N/A	ENSP00000387710.2	P26639-2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000485 AC: 6 AN: 1237288 Hom.: 0 AF XY: 0.00000329 AC XY: 2 AN XY: 607478

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

African (AFR) AF: 0.00 AC: 0 AN: 26950

American (AMR) AF: 0.0000479 AC: 1 AN: 20894

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19558

East Asian (EAS) AF: 0.00 AC: 0 AN: 32470

South Asian (SAS) AF: 0.00 AC: 0 AN: 54718

European-Finnish (FIN) AF: 0.0000285 AC: 1 AN: 35136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4380

European-Non Finnish (NFE) AF: 0.00000403 AC: 4 AN: 992692

Other (OTH) AF: 0.00 AC: 0 AN: 50490

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000670321), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6

Splicing

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

Other links and lift over

dbSNP: rs35931457; hg19: chr5-33453368;