chr3-45500511-C-T

Position:

chr3-45500511-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_015340.4(LARS2):c.1692C>T(p.Ala564Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,590,548 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0026 ( 7 hom. )

Consequence

LARS2
NM_015340.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.35

Variant links:

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 links:

LARS2-AS1 (HGNC:):

LARS2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 3-45500511-C-T is Benign according to our data. Variant chr3-45500511-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 226696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45500511-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.35 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00196 (299/152250) while in subpopulation NFE AF= 0.00329 (224/68020). AF 95% confidence interval is 0.00294. There are 2 homozygotes in gnomad4. There are 146 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARS2	NM_015340.4 linkuse as main transcript	c.1692C>T	p.Ala564Ala	synonymous_variant	15/22	ENST00000645846.2	NP_056155.1	Q15031

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LARS2	ENST00000645846.2 linkuse as main transcript	c.1692C>T	p.Ala564Ala	synonymous_variant	15/22		NM_015340.4	ENSP00000495093.1		Q15031

Frequencies

GnomAD3 genomes

AF:

0.00197

AC:

300

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000472

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00329

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00209

AC:

480

AN:

229582

Hom.:

AF XY:

0.00217

AC XY:

270

AN XY:

124380

show subpopulations

Gnomad AFR exome

AF:

0.000203

Gnomad AMR exome

AF:

0.00144

Gnomad ASJ exome

AF:

0.000826

Gnomad EAS exome

AF:

0.0000616

Gnomad SAS exome

AF:

0.00147

Gnomad FIN exome

AF:

0.000795

Gnomad NFE exome

AF:

0.00334

Gnomad OTH exome

AF:

0.00239

GnomAD4 exome

AF:

0.00264

AC:

3799

AN:

1438298

Hom.:

Cov.:

AF XY:

0.00265

AC XY:

1893

AN XY:

715050

show subpopulations

Gnomad4 AFR exome

AF:

0.000219

Gnomad4 AMR exome

AF:

0.00126

Gnomad4 ASJ exome

AF:

0.00167

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00146

Gnomad4 FIN exome

AF:

0.000544

Gnomad4 NFE exome

AF:

0.00308

Gnomad4 OTH exome

AF:

0.00249

GnomAD4 genome

AF:

0.00196

AC:

299

AN:

152250

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

146

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.000472

Gnomad4 NFE

AF:

0.00329

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00305

Hom.:

Bravo

AF:

0.00186

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	LARS2: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 23, 2019	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2017	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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ala564Ala in exon 15 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 0.3% (26/8600) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs149911756). -

LARS2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 16, 2020

This variant is classified as likely 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

BayesDel_noAF

Benign

-0.39

CADD

Benign

1.1

DANN

Benign

0.78

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over