rs78587006

Positions:

• chr3-45547365-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015340.4(LARS2):​c.2547T>C​(p.Ala849Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,609,898 control chromosomes in the GnomAD database, including 216 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (204 hom.)
• Consequence: LARS2 NM_015340.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.518

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 3-45547365-T-C is Benign according to our data. Variant chr3-45547365-T-C is described in ClinVar as [Benign]. Clinvar id is 226705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.518 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0722 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARS2	NM_015340.4	c.2547T>C	p.Ala849Ala	synonymous_variant	22/22	ENST00000645846.2	NP_056155.1
LARS2	NM_001368263.1	c.2547T>C	p.Ala849Ala	synonymous_variant	21/21		NP_001355192.1
LARS2	XM_017006042.2	c.*4T>C		3_prime_UTR_variant	21/21		XP_016861531.1
LARS2	XM_047447830.1	c.*4T>C		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	c.2547T>C	p.Ala849Ala	synonymous_variant	22/22		NM_015340.4	ENSP00000495093.1

Frequencies

GnomAD3 genomes AF: 0.00314 AC: 478 AN: 152190 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0785

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00616 AC: 1519 AN: 246402 Hom.: 52 AF XY: 0.00558 AC XY: 744 AN XY: 133430

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00338

Gnomad EAS exome AF: 0.0784

Gnomad SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00266

GnomAD4 exome AF: 0.00297 AC: 4328 AN: 1457590 Hom.: 204 Cov.: 31 AF XY: 0.00293 AC XY: 2123 AN XY: 725278

Gnomad4 AFR exome AF: 0.0000605

Gnomad4 AMR exome AF: 0.000184

Gnomad4 ASJ exome AF: 0.00413

Gnomad4 EAS exome AF: 0.0939

Gnomad4 SAS exome AF: 0.00202

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000837

Gnomad4 OTH exome AF: 0.00369

GnomAD4 genome AF: 0.00313 AC: 477 AN: 152308 Hom.: 12 Cov.: 32 AF XY: 0.00340 AC XY: 253 AN XY: 74484

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.0785

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000624 Hom.: 0

Bravo AF: 0.00313

Asia WGS AF: 0.0240 AC: 83 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000297

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 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	Nov 24, 2014	Ala849Ala in exon 22 of LARS2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 10.1% (18/178) of J apanese chromosomes from a broad population by the 1000 Genomes Project (http:// www.ncbi.nlm.nih.gov/projects/SNP; dbSNP rs78587006). -

LARS2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 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
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.51

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: rs78587006; hg19: chr3-45588857;