chr3-45476581-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015340.4(LARS2):c.972C>A(p.His324Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0316 in 1,614,124 control chromosomes in the GnomAD database, including 1,061 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 60 hom., cov: 32)

Exomes 𝑓: 0.033 ( 1001 hom. )

Consequence

LARS2
NM_015340.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.424

Publications

10 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032488406).

BP6

Variant 3-45476581-C-A is Benign according to our data. Variant chr3-45476581-C-A is described in ClinVar as Benign. ClinVar VariationId is 226708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0217 (3311/152300) while in subpopulation NFE AF = 0.0356 (2424/68020). AF 95% confidence interval is 0.0345. There are 60 homozygotes in GnomAd4. There are 1560 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 60 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LARS2	NM_015340.4 link	c.972C>A	p.His324Gln	missense_variant	Exon 10 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.972C>A	p.His324Gln	missense_variant	Exon 10 of 22		NM_015340.4	ENSP00000495093.1		Q15031

Frequencies

GnomAD3 genomes

AF:

0.0218

AC:

3311

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00526

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0102

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00786

Gnomad FIN

AF:

0.0392

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.0356

Gnomad OTH

AF:

0.0162

GnomAD2 exomes

AF:

0.0224

AC:

5617

AN:

251192

AF XY:

0.0224

show subpopulations

Gnomad AFR exome

AF:

0.00529

Gnomad AMR exome

AF:

0.00911

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0426

Gnomad NFE exome

AF:

0.0334

Gnomad OTH exome

AF:

0.0254

GnomAD4 exome

AF:

0.0326

AC:

47678

AN:

1461824

Hom.:

1001

Cov.:

AF XY:

0.0318

AC XY:

23101

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.00472

AC:

158

AN:

33480

American (AMR)

AF:

0.00921

AC:

412

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39698

South Asian (SAS)

AF:

0.0106

AC:

916

AN:

86256

European-Finnish (FIN)

AF:

0.0431

AC:

2304

AN:

53420

Middle Eastern (MID)

AF:

0.00555

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0377

AC:

41887

AN:

1111950

Other (OTH)

AF:

0.0314

AC:

1898

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

2416

4832

7247

9663

12079

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1552

3104

4656

6208

7760

<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:

0.0217

AC:

3311

AN:

152300

Hom.:

Cov.:

AF XY:

0.0209

AC XY:

1560

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00524

AC:

218

AN:

41566

American (AMR)

AF:

0.0102

AC:

156

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00787

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0392

AC:

416

AN:

10622

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0356

AC:

2424

AN:

68020

Other (OTH)

AF:

0.0161

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

163

327

490

654

817

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0266

Hom.:

151

Bravo

AF:

0.0194

TwinsUK

AF:

0.0321

AC:

119

ALSPAC

AF:

0.0368

AC:

142

ESP6500AA

AF:

0.00704

AC:

ESP6500EA

AF:

0.0349

AC:

300

ExAC

AF:

0.0223

AC:

2712

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0305

EpiControl

AF:

0.0301

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 13, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 22, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:3

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.His324Gln in exon 10 of LARS2: This variant is not expected to have clinical s ignificance because it has been identified in 3.5% (300/8600) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs71645922). -

May 14, 2018

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 02, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.081

T;T;.;T;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.43

LIST_S2

Uncertain

0.86

.;.;D;.;D

MetaRNN

Benign

0.0032

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;N;.;N;N

PhyloP100

0.42

PrimateAI

Benign

0.33

PROVEAN

Benign

0.17

N;N;N;.;.

REVEL

Benign

0.041

Sift

Benign

0.42

T;T;T;.;.

Sift4G

Benign

0.66

T;T;T;.;.

Polyphen

0.072

B;B;B;B;B

Vest4

0.16

MutPred

0.44

Loss of catalytic residue at H324 (P = 0.0902);Loss of catalytic residue at H324 (P = 0.0902);.;Loss of catalytic residue at H324 (P = 0.0902);Loss of catalytic residue at H324 (P = 0.0902);

MPC

0.26

ClinPred

0.0035

GERP RS

3.6

Varity_R

0.052

Mutation Taster

=99/1

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