rs9827689

chr3-45541917-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015340.4(LARS2):c.2493G>T(p.Glu831Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00215 in 1,614,234 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (30 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (35 hom.)
• Consequence: LARS2 NM_015340.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.267

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002663821).
• BP6: Variant 3-45541917-G-T is Benign according to our data. Variant chr3-45541917-G-T is described in ClinVar as [Benign]. Clinvar id is 218718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45541917-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0111 (1698/152362) while in subpopulation AFR AF= 0.0384 (1598/41572). AF 95% confidence interval is 0.0369. There are 30 homozygotes in gnomad4. There are 796 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARS2	NM_015340.4	c.2493G>T	p.Glu831Asp	missense_variant	21/22	ENST00000645846.2
LARS2	NM_001368263.1	c.2493G>T	p.Glu831Asp	missense_variant	20/21
LARS2	XM_017006042.2	c.2405-5434G>T		intron_variant
LARS2	XM_047447830.1	c.2405-5434G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARS2	ENST00000645846.2	c.2493G>T	p.Glu831Asp	missense_variant	21/22		NM_015340.4	P1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1689 AN: 152244 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0383

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00294 AC: 740 AN: 251320 Hom.: 11 AF XY: 0.00203 AC XY: 276 AN XY: 135836

Gnomad AFR exome AF: 0.0399

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00122 AC: 1778 AN: 1461872 Hom.: 35 Cov.: 31 AF XY: 0.00110 AC XY: 797 AN XY: 727234

Gnomad4 AFR exome AF: 0.0419

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000701

Gnomad4 OTH exome AF: 0.00286

GnomAD4 genome AF: 0.0111 AC: 1698 AN: 152362 Hom.: 30 Cov.: 32 AF XY: 0.0107 AC XY: 796 AN XY: 74528

Gnomad4 AFR AF: 0.0384

Gnomad4 AMR AF: 0.00398

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.0239 Hom.: 2356

Bravo AF: 0.0126

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0411 AC: 181

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00362 AC: 439

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000297

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Glu831Asp in exon 21 of LARS2: This variant is not expected to have clinical sig nificance because it has been identified in 4.1% (181/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs9827689). -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2016	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. -

not provided Benign:4

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 25, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -

LARS2-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 22, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Perrault syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital

Jul 23, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	12
Dann	Benign	0.87
DEOGEN2	Benign	0.053	T;T;.;T;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.79	D
MetaRNN	Benign	0.0027	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.80	N;N;.;N;N
MutationTaster	Benign	0.86	D;D;D
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.44	N;N;N;.;.
REVEL	Benign	0.016
Sift	Benign	0.39	T;T;T;.;.
Sift4G	Benign	0.63	T;T;T;.;.
Polyphen		0.0010	B;B;B;B;B
Vest4		0.079
MutPred		0.19		Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);.;Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);
MVP		0.54
MPC		0.20
ClinPred		0.0033	T
GERP RS		3.5
Varity_R		0.068

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: rs9827689; hg19: chr3-45583409; COSMIC: COSV99039350; COSMIC: COSV99039350;