chr3-45476554-G-A

Position:

• chr3-45476554-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_015340.4(LARS2):​c.945G>A​(p.Ser315=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,614,022 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S315S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (6 hom.)
• Consequence: LARS2 NM_015340.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.286

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 3-45476554-G-A is Benign according to our data. Variant chr3-45476554-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000966 (147/152224) while in subpopulation AMR AF= 0.00164 (25/15290). AF 95% confidence interval is 0.00118. There are 0 homozygotes in gnomad4. There are 55 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARS2	NM_015340.4	c.945G>A	p.Ser315=	synonymous_variant	10/22	ENST00000645846.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARS2	ENST00000645846.2	c.945G>A	p.Ser315=	synonymous_variant	10/22		NM_015340.4	P1

Frequencies

GnomAD3 genomes AF: 0.000966 AC: 147 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00106 AC: 266 AN: 250936 Hom.: 0 AF XY: 0.000980 AC XY: 133 AN XY: 135648

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00127 AC: 1850 AN: 1461798 Hom.: 6 Cov.: 31 AF XY: 0.00120 AC XY: 871 AN XY: 727204

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.00302

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00140

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.000966 AC: 147 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.000739 AC XY: 55 AN XY: 74428

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000801 Hom.: 0

Bravo AF: 0.00106

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	LARS2: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 23, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 31, 2015

p.Ser315Ser in exon 10 of LARS2: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 0.17% (20/11556) of Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs145135580). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	8.4
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs145135580; hg19: chr3-45518046;