rs10988

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020117.11(LARS1):c.3263G>A(p.Arg1088Lys) variant causes a missense change. The variant allele was found at a frequency of 0.275 in 1,612,416 control chromosomes in the GnomAD database, including 64,821 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 4845 hom., cov: 32)

Exomes 𝑓: 0.28 ( 59976 hom. )

Consequence

LARS1
NM_020117.11 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 5.00

Publications

48 publications found

Variant links:

Genes affected

LARS1 (HGNC:6512): (leucyl-tRNA synthetase 1) This gene encodes a cytosolic leucine-tRNA synthetase, a member of the class I aminoacyl-tRNA synthetase family. The encoded enzyme catalyzes the ATP-dependent ligation of L-leucine to tRNA(Leu). It is found in the cytoplasm as part of a multisynthetase complex and interacts with the arginine tRNA synthetase through its C-terminal domain. A mutation in this gene was found in affected individuals with infantile liver failure syndrome 1. Alternatively spliced transcript variants of this gene have been observed. [provided by RefSeq, Dec 2015]

LARS1 Gene-Disease associations (from GenCC):

infantile liver failure syndrome 1
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

LARS1 links:

ENSG00000251556 (HGNC:):

ENSG00000251556 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032483041).

BP6

Variant 5-146120433-C-T is Benign according to our data. Variant chr5-146120433-C-T is described in ClinVar as Benign. ClinVar VariationId is 138099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LARS1	NM_020117.11 link	c.3263G>A	p.Arg1088Lys	missense_variant	Exon 31 of 32	ENST00000394434.7	NP_064502.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LARS1	ENST00000394434.7 link	c.3263G>A	p.Arg1088Lys	missense_variant	Exon 31 of 32	1	NM_020117.11	ENSP00000377954.2

Frequencies

GnomAD3 genomes

AF:

0.225

AC:

34153

AN:

151922

Hom.:

4831

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0612

Gnomad AMI

AF:

0.443

Gnomad AMR

AF:

0.335

Gnomad ASJ

AF:

0.173

Gnomad EAS

AF:

0.214

Gnomad SAS

AF:

0.176

Gnomad FIN

AF:

0.318

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.290

Gnomad OTH

AF:

0.223

GnomAD2 exomes

AF:

0.274

AC:

68704

AN:

250466

AF XY:

0.265

show subpopulations

Gnomad AFR exome

AF:

0.0601

Gnomad AMR exome

AF:

0.455

Gnomad ASJ exome

AF:

0.170

Gnomad EAS exome

AF:

0.219

Gnomad FIN exome

AF:

0.313

Gnomad NFE exome

AF:

0.288

Gnomad OTH exome

AF:

0.269

GnomAD4 exome

AF:

0.280

AC:

408891

AN:

1460380

Hom.:

59976

Cov.:

AF XY:

0.276

AC XY:

200257

AN XY:

726522

show subpopulations

African (AFR)

AF:

0.0561

AC:

1876

AN:

33420

American (AMR)

AF:

0.444

AC:

19788

AN:

44546

Ashkenazi Jewish (ASJ)

AF:

0.171

AC:

4467

AN:

26104

East Asian (EAS)

AF:

0.224

AC:

8891

AN:

39648

South Asian (SAS)

AF:

0.178

AC:

15301

AN:

86120

European-Finnish (FIN)

AF:

0.320

AC:

17062

AN:

53398

Middle Eastern (MID)

AF:

0.132

AC:

762

AN:

5758

European-Non Finnish (NFE)

AF:

0.293

AC:

325538

AN:

1111052

Other (OTH)

AF:

0.252

AC:

15206

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

13909

27818

41726

55635

69544

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10658

21316

31974

42632

53290

<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:

0.225

AC:

34173

AN:

152036

Hom.:

4845

Cov.:

AF XY:

0.225

AC XY:

16748

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.0610

AC:

2532

AN:

41512

American (AMR)

AF:

0.336

AC:

5123

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.173

AC:

599

AN:

3472

East Asian (EAS)

AF:

0.214

AC:

1107

AN:

5162

South Asian (SAS)

AF:

0.176

AC:

848

AN:

4822

European-Finnish (FIN)

AF:

0.318

AC:

3357

AN:

10558

Middle Eastern (MID)

AF:

0.122

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.290

AC:

19704

AN:

67944

Other (OTH)

AF:

0.221

AC:

466

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1245

2489

3734

4978

6223

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

352

704

1056

1408

1760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.259

Hom.:

18939

Bravo

AF:

0.224

TwinsUK

AF:

0.293

AC:

1088

ALSPAC

AF:

0.290

AC:

1119

ESP6500AA

AF:

0.0679

AC:

299

ESP6500EA

AF:

0.279

AC:

2397

ExAC

AF:

0.264

AC:

32095

Asia WGS

AF:

0.183

AC:

639

AN:

3478

EpiCase

AF:

0.264

EpiControl

AF:

0.265

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Aug 29, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0082

T;.;.

Eigen

Benign

-0.0092

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.62

T;T;T

MetaRNN

Benign

0.0032

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

M;.;.

PhyloP100

5.0

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.41

N;.;N

REVEL

Benign

0.092

Sift

Benign

0.30

T;.;T

Sift4G

Benign

0.45

T;T;T

Vest4

0.26

ClinPred

0.024

GERP RS

4.5

Varity_R

0.20

gMVP

0.74

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over