3-45524062-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_015340.4(LARS2):c.2358A>G(p.Val786Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.976 in 1,613,866 control chromosomes in the GnomAD database, including 773,893 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.88 ( 61659 hom., cov: 30)

Exomes 𝑓: 0.99 ( 712234 hom. )

Consequence

LARS2
NM_015340.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.552

Publications

19 publications found

Variant links:

Genes affected

LARS2 (HGNC:17095): (leucyl-tRNA synthetase 2, mitochondrial) This gene encodes a class 1 aminoacyl-tRNA synthetase, mitochondrial leucyl-tRNA synthetase. Each of the twenty aminoacyl-tRNA synthetases catalyzes the aminoacylation of a specific tRNA or tRNA isoaccepting family with the cognate amino acid. [provided by RefSeq, Jul 2008]

LARS2 Gene-Disease associations (from GenCC):

hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
Perrault syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
Perrault syndrome 4
Inheritance: AR Classification: STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)

LARS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 3-45524062-A-G is Benign according to our data. Variant chr3-45524062-A-G is described in ClinVar as Benign. ClinVar VariationId is 226704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.552 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.991 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LARS2	NM_015340.4 link	c.2358A>G	p.Val786Val	synonymous_variant	Exon 20 of 22	ENST00000645846.2	NP_056155.1	Q15031

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LARS2	ENST00000645846.2 link	c.2358A>G	p.Val786Val	synonymous_variant	Exon 20 of 22		NM_015340.4	ENSP00000495093.1		Q15031

Frequencies

GnomAD3 genomes

AF:

0.883

AC:

134263

AN:

152002

Hom.:

61622

Cov.:

show subpopulations

Gnomad AFR

AF:

0.602

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.952

Gnomad ASJ

AF:

0.997

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.958

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.968

Gnomad NFE

AF:

0.998

Gnomad OTH

AF:

0.909

GnomAD2 exomes

AF:

0.965

AC:

242562

AN:

251454

AF XY:

0.972

show subpopulations

Gnomad AFR exome

AF:

0.592

Gnomad AMR exome

AF:

0.977

Gnomad ASJ exome

AF:

0.996

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

0.998

Gnomad OTH exome

AF:

0.977

GnomAD4 exome

AF:

0.985

AC:

1440007

AN:

1461746

Hom.:

712234

Cov.:

AF XY:

0.986

AC XY:

716874

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.589

AC:

19696

AN:

33454

American (AMR)

AF:

0.973

AC:

43519

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.995

AC:

26013

AN:

26134

East Asian (EAS)

AF:

1.00

AC:

39690

AN:

39698

South Asian (SAS)

AF:

0.965

AC:

83264

AN:

86256

European-Finnish (FIN)

AF:

1.00

AC:

53418

AN:

53420

Middle Eastern (MID)

AF:

0.972

AC:

5605

AN:

5768

European-Non Finnish (NFE)

AF:

0.999

AC:

1110277

AN:

1111910

Other (OTH)

AF:

0.969

AC:

58525

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

777

1554

2332

3109

3886

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21620

43240

64860

86480

108100

<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:

0.883

AC:

134359

AN:

152120

Hom.:

61659

Cov.:

AF XY:

0.887

AC XY:

65972

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.603

AC:

24948

AN:

41398

American (AMR)

AF:

0.952

AC:

14547

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.997

AC:

3461

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5166

AN:

5166

South Asian (SAS)

AF:

0.958

AC:

4625

AN:

4828

European-Finnish (FIN)

AF:

1.00

AC:

10616

AN:

10616

Middle Eastern (MID)

AF:

0.969

AC:

285

AN:

294

European-Non Finnish (NFE)

AF:

0.998

AC:

67880

AN:

68042

Other (OTH)

AF:

0.910

AC:

1919

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

562

1123

1685

2246

2808

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

876

1752

2628

3504

4380

<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:

0.944

Hom.:

38818

Bravo

AF:

0.865

Asia WGS

AF:

0.958

AC:

3332

AN:

3478

EpiCase

AF:

0.997

EpiControl

AF:

0.997

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Dec 02, 2015

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Val786Val in exon 20 of LARS2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 38.2% (1681/4406) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs267220). -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Perrault syndrome 4

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

5.6

(source)

DANN

Benign

0.78

PhyloP100

0.55

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=98/2

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over