rs114881088

chr3-45400265-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_015340.4(LARS2):c.255C>T(p.Tyr85=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,612,472 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 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (9 hom.)
• Consequence: LARS2 NM_015340.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.113

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 3-45400265-C-T is Benign according to our data. Variant chr3-45400265-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 227492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45400265-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.113 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00148 (226/152360) while in subpopulation NFE AF= 0.00216 (147/68038). AF 95% confidence interval is 0.00188. There are 0 homozygotes in gnomad4. There are 102 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARS2	NM_015340.4	c.255C>T	p.Tyr85=	synonymous_variant	4/22	ENST00000645846.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARS2	ENST00000645846.2	c.255C>T	p.Tyr85=	synonymous_variant	4/22		NM_015340.4	P1

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 226 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00111 AC: 277 AN: 249078 Hom.: 0 AF XY: 0.00102 AC XY: 137 AN XY: 134582

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.000502

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00201

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.00196 AC: 2855 AN: 1460112 Hom.: 9 Cov.: 30 AF XY: 0.00182 AC XY: 1324 AN XY: 726278

Gnomad4 AFR exome AF: 0.000869

Gnomad4 AMR exome AF: 0.000362

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000583

Gnomad4 FIN exome AF: 0.000375

Gnomad4 NFE exome AF: 0.00243

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00148 AC: 226 AN: 152360 Hom.: 0 Cov.: 32 AF XY: 0.00137 AC XY: 102 AN XY: 74500

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00216

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00172 Hom.: 0

Bravo AF: 0.00151

EpiCase AF: 0.00240

EpiControl AF: 0.00166

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	LARS2: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 13, 2019	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 16, 2017

p.Tyr85Tyr in exon 4 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 0.2% (259/126146) o f European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomAD .broadinstitute.org; dbSNP rs114881088). -

LARS2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 01, 2019

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	-0.47
Cadd	Benign	1.8
Dann	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs114881088; hg19: chr3-45441757;