rs34965084

Positions:

chr3-45547420-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015340.4(LARS2):c.2602G>A(p.Glu868Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000525 in 1,613,862 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 2 hom. )

Consequence

LARS2
NM_015340.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.48

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 (HGNC:):

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=0.0036411285).

BP6

Variant 3-45547420-G-A is Benign according to our data. Variant chr3-45547420-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 385400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45547420-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00246 (374/152280) while in subpopulation AFR AF= 0.00785 (326/41548). AF 95% confidence interval is 0.00715. There are 3 homozygotes in gnomad4. There are 181 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARS2	NM_015340.4 linkuse as main transcript	c.2602G>A	p.Glu868Lys	missense_variant	22/22	ENST00000645846.2	NP_056155.1	Q15031
LARS2	NM_001368263.1 linkuse as main transcript	c.2602G>A	p.Glu868Lys	missense_variant	21/21		NP_001355192.1
LARS2	XM_017006042.2 linkuse as main transcript	c.*59G>A		3_prime_UTR_variant	21/21		XP_016861531.1
LARS2	XM_047447830.1 linkuse as main transcript	c.*59G>A		3_prime_UTR_variant	20/20		XP_047303786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LARS2	ENST00000645846.2 linkuse as main transcript	c.2602G>A	p.Glu868Lys	missense_variant	22/22		NM_015340.4	ENSP00000495093.1		Q15031

Frequencies

GnomAD3 genomes

AF:

0.00246

AC:

374

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00787

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.000721

AC:

181

AN:

250966

Hom.:

AF XY:

0.000553

AC XY:

AN XY:

135604

show subpopulations

Gnomad AFR exome

AF:

0.00862

Gnomad AMR exome

AF:

0.000611

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000324

AC:

474

AN:

1461582

Hom.:

Cov.:

AF XY:

0.000325

AC XY:

236

AN XY:

727074

show subpopulations

Gnomad4 AFR exome

AF:

0.00930

Gnomad4 AMR exome

AF:

0.000694

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000468

Gnomad4 OTH exome

AF:

0.000944

GnomAD4 genome

AF:

0.00246

AC:

374

AN:

152280

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

181

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00785

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.000523

Hom.:

Bravo

AF:

0.00273

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00953

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000906

AC:

110

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	LARS2: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2021	This variant is associated with the following publications: (PMID: 19847392) -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Glu868Lys in exon 22 of LARS2: This variant is not expected to have clinical sig nificance because it has been identified in 1.0% (42/4406) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs34965084). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 28, 2017	- -

Perrault syndrome 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Jul 23, 2020

- -

LARS2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

T;T;.;T;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.77

.;.;T;.;T

MetaRNN

Benign

0.0036

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;L;.;L;L

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.63

N;N;N;.;.

REVEL

Benign

0.097

Sift

Benign

0.29

T;T;T;.;.

Sift4G

Benign

0.55

T;T;T;.;.

Polyphen

0.97

D;D;D;D;D

Vest4

0.16

MVP

0.47

MPC

0.25

ClinPred

0.020

GERP RS

2.7

Varity_R

0.028

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