Genetic Variant TARS1:p.Val118Phe (chr5-33453311-G-T) – 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.352G>T(p.Val118Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000212 in 1,412,010 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V118I) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TARS1
NM_152295.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.85

Publications

3 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 Submitted by: G2P
trichothiodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TARS1 links:

Genome browser will be placed here

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	HGVSp	Effect	Exon Rank	Protein
TARS1	NM_152295.5	MANE Select	c.352G>T	p.Val118Phe	missense	Exon 4 of 19	NP_689508.3
TARS1	NM_001258438.2		c.451G>T	p.Val151Phe	missense	Exon 5 of 20	NP_001245367.1
TARS1	NM_001258437.1		c.352G>T	p.Val118Phe	missense	Exon 5 of 20	NP_001245366.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TARS1	ENST00000265112.8	TSL:1 MANE Select	c.352G>T	p.Val118Phe	missense	Exon 4 of 19	ENSP00000265112.3
TARS1	ENST00000509731.5	TSL:1	n.*305G>T		non_coding_transcript_exon	Exon 5 of 19	ENSP00000427304.1
TARS1	ENST00000509731.5	TSL:1	n.*305G>T		3_prime_UTR	Exon 5 of 19	ENSP00000427304.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

134206

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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:

0.00000212

AC:

AN:

1412010

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

701520

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:

32056

American (AMR)

AF:

0.00

AC:

AN:

42324

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24902

East Asian (EAS)

AF:

0.00

AC:

AN:

37174

South Asian (SAS)

AF:

0.00

AC:

AN:

80296

European-Finnish (FIN)

AF:

0.0000197

AC:

AN:

50708

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5156

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1081584

Other (OTH)

AF:

0.00

AC:

AN:

57810

⚠️ 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: 0.258

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

134206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

63562

African (AFR)

AF:

0.00

AC:

AN:

35310

American (AMR)

AF:

0.00

AC:

AN:

11932

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3396

East Asian (EAS)

AF:

0.00

AC:

AN:

4566

South Asian (SAS)

AF:

0.00

AC:

AN:

4240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

222

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65282

Other (OTH)

AF:

0.00

AC:

AN:

1776

Alfa

AF:

0.00

Hom.:

2357

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0079

Eigen

Benign

0.19

Eigen_PC

Benign

0.14

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.37

M_CAP

Benign

0.059

MetaRNN

Uncertain

0.44

PhyloP100

6.9

Sift4G

Benign

0.61

Vest4

0.45

MVP

0.69

ClinPred

0.99

GERP RS

4.1

Varity_R

0.78

Mutation Taster

=39/61

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over