rs71645922

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 14/19 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 226708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45476581-C-A is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 60 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARS2	NM_015340.4 linkuse as main transcript	c.972C>A	p.His324Gln	missense_variant	10/22	ENST00000645846.2	NP_056155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LARS2	ENST00000645846.2 linkuse as main transcript	c.972C>A	p.His324Gln	missense_variant	10/22		NM_015340.4	ENSP00000495093	P1

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

GnomAD3 exomes

AF:

0.0224

AC:

5617

AN:

251192

Hom.:

AF XY:

0.0224

AC XY:

3035

AN XY:

135740

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 SAS exome

AF:

0.0106

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

Gnomad4 AFR exome

AF:

0.00472

Gnomad4 AMR exome

AF:

0.00921

Gnomad4 ASJ exome

AF:

0.00260

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0106

Gnomad4 FIN exome

AF:

0.0431

Gnomad4 NFE exome

AF:

0.0377

Gnomad4 OTH exome

AF:

0.0314

GnomAD4 genome

AF:

0.0217

AC:

3311

AN:

152300

Hom.:

Cov.:

AF XY:

0.0209

AC XY:

1560

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00524

Gnomad4 AMR

AF:

0.0102

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00787

Gnomad4 FIN

AF:

0.0392

Gnomad4 NFE

AF:

0.0356

Gnomad4 OTH

AF:

0.0161

Alfa

AF:

0.0275

Hom.:

101

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 13, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	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). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 14, 2018	- -

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

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

MutationTaster

Benign

0.99

N;N;N

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over