rs2128361

chr3-45491732-G-Achr3-45491732-G-Cchr3-45491732-G-T

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.1455G>A(p.Ala485=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.922 in 1,614,084 control chromosomes in the GnomAD database, including 697,058 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (52827 hom., cov: 32)
  • Exomes 𝑓: 0.93 (644231 hom.)
• Consequence: LARS2 NM_015340.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.83

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-AS1 (HGNC:40796): (LARS2 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-45491732-G-A is Benign according to our data. Variant chr3-45491732-G-A is described in ClinVar as [Benign]. Clinvar id is 226693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.83 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARS2	NM_015340.4	c.1455G>A	p.Ala485=	synonymous_variant	13/22	ENST00000645846.2
LARS2-AS1	NR_048543.1	n.517+3512C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARS2	ENST00000645846.2	c.1455G>A	p.Ala485=	synonymous_variant	13/22		NM_015340.4	P1
LARS2-AS1	ENST00000442534.2	n.517+3512C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.799 AC: 121611 AN: 152118 Hom.: 52811 Cov.: 32

Gnomad AFR AF: 0.422

Gnomad AMI AF: 0.986

Gnomad AMR AF: 0.905

Gnomad ASJ AF: 0.889

Gnomad EAS AF: 0.976

Gnomad SAS AF: 0.920

Gnomad FIN AF: 0.976

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.948

Gnomad OTH AF: 0.826

GnomAD3 exomes AF: 0.912 AC: 229280 AN: 251372 Hom.: 106850 AF XY: 0.921 AC XY: 125105 AN XY: 135862

Gnomad AFR exome AF: 0.413

Gnomad AMR exome AF: 0.946

Gnomad ASJ exome AF: 0.885

Gnomad EAS exome AF: 0.978

Gnomad SAS exome AF: 0.930

Gnomad FIN exome AF: 0.973

Gnomad NFE exome AF: 0.948

Gnomad OTH exome AF: 0.918

GnomAD4 exome AF: 0.935 AC: 1366633 AN: 1461848 Hom.: 644231 Cov.: 59 AF XY: 0.936 AC XY: 680828 AN XY: 727228

Gnomad4 AFR exome AF: 0.403

Gnomad4 AMR exome AF: 0.940

Gnomad4 ASJ exome AF: 0.882

Gnomad4 EAS exome AF: 0.978

Gnomad4 SAS exome AF: 0.929

Gnomad4 FIN exome AF: 0.971

Gnomad4 NFE exome AF: 0.951

Gnomad4 OTH exome AF: 0.908

GnomAD4 genome AF: 0.799 AC: 121660 AN: 152236 Hom.: 52827 Cov.: 32 AF XY: 0.805 AC XY: 59958 AN XY: 74456

Gnomad4 AFR AF: 0.421

Gnomad4 AMR AF: 0.905

Gnomad4 ASJ AF: 0.889

Gnomad4 EAS AF: 0.976

Gnomad4 SAS AF: 0.920

Gnomad4 FIN AF: 0.976

Gnomad4 NFE AF: 0.948

Gnomad4 OTH AF: 0.828

Alfa AF: 0.872 Hom.: 27389

Bravo AF: 0.775

Asia WGS AF: 0.915 AC: 3180 AN: 3478

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	Ala485Ala in exon 13 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 44.0% (1938/4406) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2128361). -

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	-0.88
Cadd	Benign	0.037
Dann	Benign	0.65

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: rs2128361; hg19: chr3-45533224; COSMIC: COSV55528821;