rs116826217

Positions:

chr3-45496303-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015340.4(LARS2):c.1552G>A(p.Asp518Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00595 in 1,613,938 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0044 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0061 ( 37 hom. )

Consequence

LARS2
NM_015340.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 9.56

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:

LARS2-AS1 (HGNC:):

LARS2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015624285).

BP6

Variant 3-45496303-G-A is Benign according to our data. Variant chr3-45496303-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226694.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=4}. Variant chr3-45496303-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00442 (673/152312) while in subpopulation NFE AF= 0.00781 (531/68016). AF 95% confidence interval is 0.00726. There are 4 homozygotes in gnomad4. There are 305 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARS2	NM_015340.4 linkuse as main transcript	c.1552G>A	p.Asp518Asn	missense_variant	14/22	ENST00000645846.2	NP_056155.1	Q15031

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LARS2	ENST00000645846.2 linkuse as main transcript	c.1552G>A	p.Asp518Asn	missense_variant	14/22		NM_015340.4	ENSP00000495093.1		Q15031

Frequencies

GnomAD3 genomes

AF:

0.00444

AC:

675

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00179

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00339

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00781

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00381

AC:

958

AN:

251478

Hom.:

AF XY:

0.00386

AC XY:

524

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00288

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00167

Gnomad FIN exome

AF:

0.00513

Gnomad NFE exome

AF:

0.00606

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00611

AC:

8925

AN:

1461626

Hom.:

Cov.:

AF XY:

0.00599

AC XY:

4357

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.00119

Gnomad4 AMR exome

AF:

0.000850

Gnomad4 ASJ exome

AF:

0.00276

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00148

Gnomad4 FIN exome

AF:

0.00489

Gnomad4 NFE exome

AF:

0.00727

Gnomad4 OTH exome

AF:

0.00500

GnomAD4 genome

AF:

0.00442

AC:

673

AN:

152312

Hom.:

Cov.:

AF XY:

0.00409

AC XY:

305

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00178

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00339

Gnomad4 NFE

AF:

0.00781

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00635

Hom.:

Bravo

AF:

0.00436

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00882

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00779

AC:

ExAC

AF:

0.00366

AC:

445

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00649

EpiControl

AF:

0.00575

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	LARS2: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 05, 2019	This variant is associated with the following publications: (PMID: 32442335) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 25, 2022	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 16, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Asp518Asn in exon 14 of LARS2: This variant is not expected to have clinical sig nificance because it has been identified in 0.8% (67/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs116826217). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 30, 2017	- -

Inborn mitochondrial myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Kids Research, The Children's Hospital at Westmead

Jul 18, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

D;D;.;D;D

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

.;.;D;.;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.016

T;T;T;T;T

MetaSVM

Benign

-0.55

MutationAssessor

Uncertain

2.2

M;M;.;M;M

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.5

D;D;D;.;.

REVEL

Uncertain

0.48

Sift

Pathogenic

0.0

D;D;D;.;.

Sift4G

Uncertain

0.036

D;D;D;.;.

Polyphen

1.0

D;D;D;D;D

Vest4

0.95

MVP

0.72

MPC

0.82

ClinPred

0.028

GERP RS

5.5

Varity_R

0.77

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