rs36054230

chr3-45518039-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.2181G>T(p.Lys727Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00243 in 1,613,668 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.013 (30 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (43 hom.)
• Consequence: LARS2 NM_015340.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.60

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=0.0028013885).
• BP6: Variant 3-45518039-G-T is Benign according to our data. Variant chr3-45518039-G-T is described in ClinVar as [Benign]. Clinvar id is 226701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0131 (2002/152260) while in subpopulation AFR AF= 0.0458 (1903/41548). AF 95% confidence interval is 0.0441. There are 30 homozygotes in gnomad4. There are 940 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARS2	NM_015340.4	c.2181G>T	p.Lys727Asn	missense_variant	18/22	ENST00000645846.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARS2	ENST00000645846.2	c.2181G>T	p.Lys727Asn	missense_variant	18/22		NM_015340.4	P1

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1995 AN: 152142 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0457

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00338 AC: 847 AN: 250954 Hom.: 18 AF XY: 0.00245 AC XY: 333 AN XY: 135656

Gnomad AFR exome AF: 0.0462

Gnomad AMR exome AF: 0.00166

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00132 AC: 1927 AN: 1461408 Hom.: 43 Cov.: 31 AF XY: 0.00115 AC XY: 838 AN XY: 727010

Gnomad4 AFR exome AF: 0.0450

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000127

Gnomad4 OTH exome AF: 0.00280

GnomAD4 genome AF: 0.0131 AC: 2002 AN: 152260 Hom.: 30 Cov.: 32 AF XY: 0.0126 AC XY: 940 AN XY: 74440

Gnomad4 AFR AF: 0.0458

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00215 Hom.: 12

Bravo AF: 0.0148

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0452 AC: 199

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00434 AC: 527

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Lys727Asn in exon 18 of LARS2: This variant is not expected to have clinical sig nificance because it has been identified in 4.5% (199/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs36054230). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 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:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 22, 2017	- -

LARS2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.085	T;T;.;T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.042
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Benign	0.0028	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;.;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.63	N;N;N;.;.
REVEL	Benign	0.064
Sift	Benign	0.40	T;T;T;.;.
Sift4G	Benign	0.31	T;T;T;.;.
Polyphen		0.0070	B;B;B;B;B
Vest4		0.17
MutPred		0.29		Gain of ubiquitination at K722 (P = 0.0301);Gain of ubiquitination at K722 (P = 0.0301);.;Gain of ubiquitination at K722 (P = 0.0301);Gain of ubiquitination at K722 (P = 0.0301);
MVP		0.46
MPC		0.30
ClinPred		0.0074	T
GERP RS		3.5
Varity_R		0.076

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs36054230; hg19: chr3-45559531;