rs202009605

Positions:

• chr3-45496381-G-A

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.1622+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000376 in 1,599,054 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (3 hom.)
• Consequence: LARS2 NM_015340.4 splice_region, intron
• Scores: Splicing: ADA: 0.00005014
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.10

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-AS1 (HGNC:40796): (LARS2 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-45496381-G-A is Benign according to our data. Variant chr3-45496381-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 387637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00038 (550/1446812) while in subpopulation MID AF= 0.00888 (51/5742). AF 95% confidence interval is 0.00694. There are 3 homozygotes in gnomad4_exome. There are 273 alleles in male gnomad4_exome subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARS2	NM_015340.4	c.1622+8G>A		splice_region_variant, intron_variant		ENST00000645846.2
LARS2-AS1	NR_048543.1	n.261-881C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARS2	ENST00000645846.2	c.1622+8G>A		splice_region_variant, intron_variant			NM_015340.4	P1
LARS2-AS1	ENST00000442534.2	n.261-881C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000466 AC: 117 AN: 251174 Hom.: 1 AF XY: 0.000449 AC XY: 61 AN XY: 135758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000840

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000360

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000380 AC: 550 AN: 1446812 Hom.: 3 Cov.: 26 AF XY: 0.000379 AC XY: 273 AN XY: 720786

Gnomad4 AFR exome AF: 0.000482

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00250

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000303

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000269

Gnomad4 OTH exome AF: 0.000852

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74428

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000638 Hom.: 0

Bravo AF: 0.000370

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 07, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 25, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	LARS2: BP4 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 22, 2019	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 18, 2016	c.1622+8G>A in intron 14 of LARS2: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus se quence. It has been identified in 31/66680 European chromosomes by the Exome Agg regation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs202009605). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.35
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000050
dbscSNV1_RF	Benign	0.020
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: rs202009605; hg19: chr3-45537873;