rs34965084

chr3-45547420-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 12/18 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.48

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARS2	NM_015340.4	c.2602G>A	p.Glu868Lys	missense_variant	22/22	ENST00000645846.2
LARS2	NM_001368263.1	c.2602G>A	p.Glu868Lys	missense_variant	21/21
LARS2	XM_017006042.2	c.*59G>A		3_prime_UTR_variant	21/21
LARS2	XM_047447830.1	c.*59G>A		3_prime_UTR_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARS2	ENST00000645846.2	c.2602G>A	p.Glu868Lys	missense_variant	22/22		NM_015340.4	P1

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 374 AN: 152162 Hom.: 3 Cov.: 32

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.: 0 AF XY: 0.000553 AC XY: 75 AN XY: 135604

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.: 2 Cov.: 31 AF XY: 0.000325 AC XY: 236 AN XY: 727074

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.: 3 Cov.: 32 AF XY: 0.00243 AC XY: 181 AN XY: 74470

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.: 0

Bravo AF: 0.00273

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00953 AC: 42

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000906 AC: 110

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2021	This variant is associated with the following publications: (PMID: 19847392) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	LARS2: BP4, BS1 -

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	- -

LARS2-related condition Benign:1

Benign, criteria provided, single submitter

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). -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	17
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	D
MetaRNN	Benign	0.0036	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L;.;L;L
MutationTaster	Benign	0.83	D;D;D
PrimateAI	Benign	0.39	T
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	T
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

Other links and lift over

dbSNP: rs34965084; hg19: chr3-45588912;