rs11549809

Positions:

• chr3-45516215-G-A

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.1983G>A​(p.Thr661Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,613,508 control chromosomes in the GnomAD database, including 72,801 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5876 hom., cov: 32)
  • Exomes 𝑓: 0.30 (66925 hom.)
• Consequence: LARS2 NM_015340.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.78

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=-0.65).
• BP6: Variant 3-45516215-G-A is Benign according to our data. Variant chr3-45516215-G-A is described in ClinVar as [Benign]. Clinvar id is 226698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.78 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARS2	NM_015340.4	c.1983G>A	p.Thr661Thr	synonymous_variant	17/22	ENST00000645846.2	NP_056155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LARS2	ENST00000645846.2	c.1983G>A	p.Thr661Thr	synonymous_variant	17/22		NM_015340.4	ENSP00000495093.1

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41129 AN: 151992 Hom.: 5873 Cov.: 32

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.378

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.309

GnomAD3 exomes AF: 0.280 AC: 70237 AN: 251242 Hom.: 10609 AF XY: 0.289 AC XY: 39245 AN XY: 135774

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.206

Gnomad ASJ exome AF: 0.364

Gnomad EAS exome AF: 0.196

Gnomad SAS exome AF: 0.305

Gnomad FIN exome AF: 0.212

Gnomad NFE exome AF: 0.322

Gnomad OTH exome AF: 0.307

GnomAD4 exome AF: 0.299 AC: 436892 AN: 1461398 Hom.: 66925 Cov.: 35 AF XY: 0.301 AC XY: 218640 AN XY: 727012

Gnomad4 AFR exome AF: 0.213

Gnomad4 AMR exome AF: 0.213

Gnomad4 ASJ exome AF: 0.362

Gnomad4 EAS exome AF: 0.204

Gnomad4 SAS exome AF: 0.304

Gnomad4 FIN exome AF: 0.223

Gnomad4 NFE exome AF: 0.310

Gnomad4 OTH exome AF: 0.300

GnomAD4 genome AF: 0.270 AC: 41139 AN: 152110 Hom.: 5876 Cov.: 32 AF XY: 0.266 AC XY: 19787 AN XY: 74330

Gnomad4 AFR AF: 0.210

Gnomad4 AMR AF: 0.293

Gnomad4 ASJ AF: 0.378

Gnomad4 EAS AF: 0.194

Gnomad4 SAS AF: 0.293

Gnomad4 FIN AF: 0.198

Gnomad4 NFE AF: 0.311

Gnomad4 OTH AF: 0.311

Alfa AF: 0.319 Hom.: 14987

Bravo AF: 0.274

Asia WGS AF: 0.214 AC: 743 AN: 3478

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	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	Thr661Thr in exon 17 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 31.8% (2733/8600) o f European American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs11549809). -

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.65
CADD	Benign	0.38
DANN	Benign	0.47

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: rs11549809; hg19: chr3-45557707; COSMIC: COSV55526276; COSMIC: COSV55526276;