3-45524062-A-G

Position:

• chr3-45524062-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_015340.4(LARS2):​c.2358A>G​(p.Val786=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.976 in 1,613,866 control chromosomes in the GnomAD database, including 773,893 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (61659 hom., cov: 30)
  • Exomes 𝑓: 0.99 (712234 hom.)
• Consequence: LARS2 NM_015340.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.552

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 3-45524062-A-G is Benign according to our data. Variant chr3-45524062-A-G is described in ClinVar as [Benign]. Clinvar id is 226704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.552 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.991 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARS2	NM_015340.4	c.2358A>G	p.Val786=	synonymous_variant	20/22	ENST00000645846.2	NP_056155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LARS2	ENST00000645846.2	c.2358A>G	p.Val786=	synonymous_variant	20/22		NM_015340.4	ENSP00000495093	P1

Frequencies

GnomAD3 genomes AF: 0.883 AC: 134263 AN: 152002 Hom.: 61622 Cov.: 30

Gnomad AFR AF: 0.602

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.952

Gnomad ASJ AF: 0.997

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.958

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.968

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.909

GnomAD3 exomes AF: 0.965 AC: 242562 AN: 251454 Hom.: 118248 AF XY: 0.972 AC XY: 132064 AN XY: 135902

Gnomad AFR exome AF: 0.592

Gnomad AMR exome AF: 0.977

Gnomad ASJ exome AF: 0.996

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.966

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.977

GnomAD4 exome AF: 0.985 AC: 1440007 AN: 1461746 Hom.: 712234 Cov.: 42 AF XY: 0.986 AC XY: 716874 AN XY: 727180

Gnomad4 AFR exome AF: 0.589

Gnomad4 AMR exome AF: 0.973

Gnomad4 ASJ exome AF: 0.995

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.965

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.999

Gnomad4 OTH exome AF: 0.969

GnomAD4 genome AF: 0.883 AC: 134359 AN: 152120 Hom.: 61659 Cov.: 30 AF XY: 0.887 AC XY: 65972 AN XY: 74378

Gnomad4 AFR AF: 0.603

Gnomad4 AMR AF: 0.952

Gnomad4 ASJ AF: 0.997

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.958

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.998

Gnomad4 OTH AF: 0.910

Alfa AF: 0.948 Hom.: 38671

Bravo AF: 0.865

Asia WGS AF: 0.958 AC: 3332 AN: 3478

EpiCase AF: 0.997

EpiControl AF: 0.997

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Val786Val in exon 20 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 38.2% (1681/4406) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs267220). -

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 16, 2016	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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	-0.43
CADD	Benign	5.6
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs267220; hg19: chr3-45565554;