rs2306522

Positions:

• chr3-45500591-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015340.4(LARS2):​c.1760+12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.621 in 1,539,344 control chromosomes in the GnomAD database, including 307,286 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (24080 hom., cov: 33)
  • Exomes 𝑓: 0.63 (283206 hom.)
• Consequence: LARS2 NM_015340.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.62

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-45500591-T-C is Benign according to our data. Variant chr3-45500591-T-C is described in ClinVar as [Benign]. Clinvar id is 226697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.76 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARS2	NM_015340.4	c.1760+12T>C		intron_variant		ENST00000645846.2
LARS2-AS1	NR_048543.1	n.261-5091A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARS2	ENST00000645846.2	c.1760+12T>C		intron_variant			NM_015340.4	P1
LARS2-AS1	ENST00000442534.2	n.261-5091A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78278 AN: 152032 Hom.: 24071 Cov.: 33

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.795

Gnomad AMR AF: 0.606

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.780

Gnomad SAS AF: 0.557

Gnomad FIN AF: 0.778

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.637

Gnomad OTH AF: 0.504

GnomAD3 exomes AF: 0.625 AC: 119615 AN: 191354 Hom.: 39309 AF XY: 0.624 AC XY: 65534 AN XY: 104972

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.748

Gnomad ASJ exome AF: 0.535

Gnomad EAS exome AF: 0.784

Gnomad SAS exome AF: 0.567

Gnomad FIN exome AF: 0.762

Gnomad NFE exome AF: 0.630

Gnomad OTH exome AF: 0.617

GnomAD4 exome AF: 0.633 AC: 877652 AN: 1387194 Hom.: 283206 Cov.: 30 AF XY: 0.631 AC XY: 434267 AN XY: 688272

Gnomad4 AFR exome AF: 0.145

Gnomad4 AMR exome AF: 0.720

Gnomad4 ASJ exome AF: 0.523

Gnomad4 EAS exome AF: 0.773

Gnomad4 SAS exome AF: 0.566

Gnomad4 FIN exome AF: 0.749

Gnomad4 NFE exome AF: 0.642

Gnomad4 OTH exome AF: 0.603

GnomAD4 genome AF: 0.515 AC: 78297 AN: 152150 Hom.: 24080 Cov.: 33 AF XY: 0.524 AC XY: 38987 AN XY: 74370

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.607

Gnomad4 ASJ AF: 0.512

Gnomad4 EAS AF: 0.780

Gnomad4 SAS AF: 0.557

Gnomad4 FIN AF: 0.778

Gnomad4 NFE AF: 0.637

Gnomad4 OTH AF: 0.502

Alfa AF: 0.557 Hom.: 5310

Bravo AF: 0.488

Asia WGS AF: 0.657 AC: 2284 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

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	1760+12T>C in intron 15 of LARS2: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence. It has been identified in 37.1% (3193/8600) of European American chromoso mes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs .washington.edu/EVS; dbSNP rs2306522). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 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	0.028
DANN	Benign	0.58

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: rs2306522; hg19: chr3-45542083;