Genetic Variant TARS1:c.330-10_330-4delTTTTTTT (chr5-33453263-CTTTTTTT-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_152295.5(TARS1):c.330-10_330-4delTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,342,490 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: 𝑓 0.0000095 ( 0 hom., cov: 22)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

TARS1
NM_152295.5 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.61

Publications

1 publications found

Variant links:

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

TARS1 links:

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ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TARS1	NM_152295.5	MANE Select	c.330-10_330-4delTTTTTTT	splice_region intron	N/A	NP_689508.3
TARS1	NM_001258438.2		c.429-10_429-4delTTTTTTT	splice_region intron	N/A	NP_001245367.1	P26639-2
TARS1	NM_001258437.1		c.330-10_330-4delTTTTTTT	splice_region intron	N/A	NP_001245366.1	P26639-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TARS1	ENST00000265112.8	TSL:1 MANE Select	c.330-25_330-19delTTTTTTT	intron	N/A	ENSP00000265112.3	P26639-1
TARS1	ENST00000509731.5	TSL:1	n.283-25_283-19delTTTTTTT	intron	N/A	ENSP00000427304.1	D6RJ97
TARS1	ENST00000455217.6	TSL:2	c.429-25_429-19delTTTTTTT	intron	N/A	ENSP00000387710.2	P26639-2

Frequencies

GnomAD3 genomes

AF:

0.00000950

AC:

AN:

105230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000336

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000113

AC:

AN:

1237260

Hom.:

AF XY:

0.0000115

AC XY:

AN XY:

607462

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

26950

American (AMR)

AF:

0.000144

AC:

AN:

20894

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19558

East Asian (EAS)

AF:

0.0000308

AC:

AN:

32470

South Asian (SAS)

AF:

0.0000548

AC:

AN:

54712

European-Finnish (FIN)

AF:

0.0000569

AC:

AN:

35134

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4380

European-Non Finnish (NFE)

AF:

0.00000403

AC:

AN:

992674

Other (OTH)

AF:

0.0000198

AC:

AN:

50488

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.250

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000950

AC:

AN:

105230

Hom.:

Cov.:

AF XY:

0.0000201

AC XY:

AN XY:

49638

show subpopulations

African (AFR)

AF:

0.0000336

AC:

AN:

29764

American (AMR)

AF:

0.00

AC:

AN:

9528

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

2676

South Asian (SAS)

AF:

0.00

AC:

AN:

2934

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4508

Middle Eastern (MID)

AF:

0.00

AC:

AN:

182

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

50862

Other (OTH)

AF:

0.00

AC:

AN:

1392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over