3-45518027-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_015340.4(LARS2):c.2169T>C(p.Ala723Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.971 in 1,613,626 control chromosomes in the GnomAD database, including 768,084 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A723A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.87 ( 60258 hom., cov: 30)

Exomes 𝑓: 0.98 ( 707826 hom. )

Consequence

LARS2
NM_015340.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.91

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 3-45518027-T-C is Benign according to our data. Variant chr3-45518027-T-C is described in ClinVar as Benign. ClinVar VariationId is 226700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.91 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.99 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LARS2	NM_015340.4 link	c.2169T>C	p.Ala723Ala	synonymous_variant	Exon 18 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.2169T>C	p.Ala723Ala	synonymous_variant	Exon 18 of 22		NM_015340.4	ENSP00000495093.1		Q15031

Frequencies

GnomAD3 genomes

AF:

0.869

AC:

132104

AN:

151966

Hom.:

60221

Cov.:

show subpopulations

Gnomad AFR

AF:

0.561

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.945

Gnomad ASJ

AF:

0.951

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.957

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.953

Gnomad NFE

AF:

0.996

Gnomad OTH

AF:

0.894

GnomAD2 exomes

AF:

0.959

AC:

240782

AN:

251180

AF XY:

0.967

show subpopulations

Gnomad AFR exome

AF:

0.553

Gnomad AMR exome

AF:

0.972

Gnomad ASJ exome

AF:

0.949

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

0.996

Gnomad OTH exome

AF:

0.969

GnomAD4 exome

AF:

0.982

AC:

1434723

AN:

1461542

Hom.:

707826

Cov.:

AF XY:

0.982

AC XY:

714349

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.545

AC:

18218

AN:

33438

American (AMR)

AF:

0.969

AC:

43287

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.949

AC:

24805

AN:

26130

East Asian (EAS)

AF:

1.00

AC:

39685

AN:

39694

South Asian (SAS)

AF:

0.965

AC:

83228

AN:

86238

European-Finnish (FIN)

AF:

1.00

AC:

53412

AN:

53414

Middle Eastern (MID)

AF:

0.957

AC:

5514

AN:

5764

European-Non Finnish (NFE)

AF:

0.997

AC:

1108563

AN:

1111790

Other (OTH)

AF:

0.961

AC:

58011

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

932

1864

2795

3727

4659

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21606

43212

64818

86424

108030

<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:

0.869

AC:

132199

AN:

152084

Hom.:

60258

Cov.:

AF XY:

0.873

AC XY:

64925

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.562

AC:

23255

AN:

41408

American (AMR)

AF:

0.945

AC:

14450

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.951

AC:

3300

AN:

3470

East Asian (EAS)

AF:

1.00

AC:

5168

AN:

5168

South Asian (SAS)

AF:

0.957

AC:

4607

AN:

4812

European-Finnish (FIN)

AF:

1.00

AC:

10610

AN:

10610

Middle Eastern (MID)

AF:

0.952

AC:

280

AN:

294

European-Non Finnish (NFE)

AF:

0.996

AC:

67736

AN:

68016

Other (OTH)

AF:

0.895

AC:

1881

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

588

1175

1763

2350

2938

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

868

1736

2604

3472

4340

<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:

0.938

Hom.:

46786

Bravo

AF:

0.849

Asia WGS

AF:

0.957

AC:

3327

AN:

3478

EpiCase

AF:

0.994

EpiControl

AF:

0.994

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ala723Ala in exon 18 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 42.5% (1871/4406) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2170549). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not provided

Benign:3

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

-0.75

CADD

Benign

1.3

(source)

DANN

Benign

0.45

PhyloP100

-1.9

Mutation Taster

=100/0

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