3-45518027-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.2169T>C(p.Ala723=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.971 in 1,613,626 control chromosomes in the GnomAD database, including 768,084 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A723A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.87 (60258 hom., cov: 30)
  • Exomes 𝑓: 0.98 (707826 hom.)
• Consequence: LARS2 NM_015340.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.91

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 3-45518027-T-C is Benign according to our data. Variant chr3-45518027-T-C is described in ClinVar as [Benign]. Clinvar id is 226700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.91 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.99 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARS2	NM_015340.4	c.2169T>C	p.Ala723=	synonymous_variant	18/22	ENST00000645846.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARS2	ENST00000645846.2	c.2169T>C	p.Ala723=	synonymous_variant	18/22		NM_015340.4	P1

Frequencies

GnomAD3 genomes AF: 0.869 AC: 132104 AN: 151966 Hom.: 60221 Cov.: 30

Gnomad AFR AF: 0.561

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.945

Gnomad ASJ AF: 0.951

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.957

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.953

Gnomad NFE AF: 0.996

Gnomad OTH AF: 0.894

GnomAD3 exomes AF: 0.959 AC: 240782 AN: 251180 Hom.: 116905 AF XY: 0.967 AC XY: 131229 AN XY: 135768

Gnomad AFR exome AF: 0.553

Gnomad AMR exome AF: 0.972

Gnomad ASJ exome AF: 0.949

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.966

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.996

Gnomad OTH exome AF: 0.969

GnomAD4 exome AF: 0.982 AC: 1434723 AN: 1461542 Hom.: 707826 Cov.: 38 AF XY: 0.982 AC XY: 714349 AN XY: 727114

Gnomad4 AFR exome AF: 0.545

Gnomad4 AMR exome AF: 0.969

Gnomad4 ASJ exome AF: 0.949

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.965

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.997

Gnomad4 OTH exome AF: 0.961

GnomAD4 genome AF: 0.869 AC: 132199 AN: 152084 Hom.: 60258 Cov.: 30 AF XY: 0.873 AC XY: 64925 AN XY: 74356

Gnomad4 AFR AF: 0.562

Gnomad4 AMR AF: 0.945

Gnomad4 ASJ AF: 0.951

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.957

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.996

Gnomad4 OTH AF: 0.895

Alfa AF: 0.943 Hom.: 41717

Bravo AF: 0.849

Asia WGS AF: 0.957 AC: 3327 AN: 3478

EpiCase AF: 0.994

EpiControl AF: 0.994

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2015	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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ala723Ala in exon 18 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 42.5% (1871/4406) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2170549). -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 16, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Perrault syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	1.3
Dann	Benign	0.45

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: rs2170549; hg19: chr3-45559519; COSMIC: COSV55527324;