rs71645922

chr3-45476581-C-Achr3-45476581-C-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.972C>A(p.His324Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0316 in 1,614,124 control chromosomes in the GnomAD database, including 1,061 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (60 hom., cov: 32)
  • Exomes 𝑓: 0.033 (1001 hom.)
• Consequence: LARS2 NM_015340.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.424

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=0.0032488406).
• BP6: Variant 3-45476581-C-A is Benign according to our data. Variant chr3-45476581-C-A is described in ClinVar as [Benign]. Clinvar id is 226708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45476581-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0217 (3311/152300) while in subpopulation NFE AF= 0.0356 (2424/68020). AF 95% confidence interval is 0.0345. There are 60 homozygotes in gnomad4. There are 1560 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 60 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARS2	NM_015340.4	c.972C>A	p.His324Gln	missense_variant	10/22	ENST00000645846.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARS2	ENST00000645846.2	c.972C>A	p.His324Gln	missense_variant	10/22		NM_015340.4	P1

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3311 AN: 152182 Hom.: 60 Cov.: 32

Gnomad AFR AF: 0.00526

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.0392

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0356

Gnomad OTH AF: 0.0162

GnomAD3 exomes AF: 0.0224 AC: 5617 AN: 251192 Hom.: 92 AF XY: 0.0224 AC XY: 3035 AN XY: 135740

Gnomad AFR exome AF: 0.00529

Gnomad AMR exome AF: 0.00911

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0106

Gnomad FIN exome AF: 0.0426

Gnomad NFE exome AF: 0.0334

Gnomad OTH exome AF: 0.0254

GnomAD4 exome AF: 0.0326 AC: 47678 AN: 1461824 Hom.: 1001 Cov.: 31 AF XY: 0.0318 AC XY: 23101 AN XY: 727224

Gnomad4 AFR exome AF: 0.00472

Gnomad4 AMR exome AF: 0.00921

Gnomad4 ASJ exome AF: 0.00260

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0106

Gnomad4 FIN exome AF: 0.0431

Gnomad4 NFE exome AF: 0.0377

Gnomad4 OTH exome AF: 0.0314

GnomAD4 genome AF: 0.0217 AC: 3311 AN: 152300 Hom.: 60 Cov.: 32 AF XY: 0.0209 AC XY: 1560 AN XY: 74476

Gnomad4 AFR AF: 0.00524

Gnomad4 AMR AF: 0.0102

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00787

Gnomad4 FIN AF: 0.0392

Gnomad4 NFE AF: 0.0356

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0275 Hom.: 101

Bravo AF: 0.0194

TwinsUK AF: 0.0321 AC: 119

ALSPAC AF: 0.0368 AC: 142

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.0349 AC: 300

ExAC AF: 0.0223 AC: 2712

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0305

EpiControl AF: 0.0301

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 13, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.His324Gln in exon 10 of LARS2: This variant is not expected to have clinical s ignificance because it has been identified in 3.5% (300/8600) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs71645922). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 14, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	14
Dann	Benign	0.82
DEOGEN2	Benign	0.081	T;T;.;T;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.43	N
MetaRNN	Benign	0.0032	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N;.;N;N
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.17	N;N;N;.;.
REVEL	Benign	0.041
Sift	Benign	0.42	T;T;T;.;.
Sift4G	Benign	0.66	T;T;T;.;.
Polyphen		0.072	B;B;B;B;B
Vest4		0.16
MutPred		0.44		Loss of catalytic residue at H324 (P = 0.0902);Loss of catalytic residue at H324 (P = 0.0902);.;Loss of catalytic residue at H324 (P = 0.0902);Loss of catalytic residue at H324 (P = 0.0902);
MPC		0.26
ClinPred		0.0035	T
GERP RS		3.6
Varity_R		0.052

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: rs71645922; hg19: chr3-45518073;