rs116826217

chr3-45496303-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015340.4(LARS2):c.1552G>A(p.Asp518Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00595 in 1,613,938 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D518D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0044 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (37 hom.)
• Consequence: LARS2 NM_015340.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 9.56

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015624285).
• BP6: Variant 3-45496303-G-A is Benign according to our data. Variant chr3-45496303-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226694.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=3, Uncertain_significance=1}. Variant chr3-45496303-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00442 (673/152312) while in subpopulation NFE AF= 0.00781 (531/68016). AF 95% confidence interval is 0.00726. There are 4 homozygotes in gnomad4. There are 305 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARS2	NM_015340.4	c.1552G>A	p.Asp518Asn	missense_variant	14/22	ENST00000645846.2
LARS2-AS1	NR_048543.1	n.261-803C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARS2	ENST00000645846.2	c.1552G>A	p.Asp518Asn	missense_variant	14/22		NM_015340.4	P1
LARS2-AS1	ENST00000442534.2	n.261-803C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00444 AC: 675 AN: 152194 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00781

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00381 AC: 958 AN: 251478 Hom.: 4 AF XY: 0.00386 AC XY: 524 AN XY: 135910

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00167

Gnomad FIN exome AF: 0.00513

Gnomad NFE exome AF: 0.00606

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00611 AC: 8925 AN: 1461626 Hom.: 37 Cov.: 30 AF XY: 0.00599 AC XY: 4357 AN XY: 727118

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.00276

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00148

Gnomad4 FIN exome AF: 0.00489

Gnomad4 NFE exome AF: 0.00727

Gnomad4 OTH exome AF: 0.00500

GnomAD4 genome AF: 0.00442 AC: 673 AN: 152312 Hom.: 4 Cov.: 32 AF XY: 0.00409 AC XY: 305 AN XY: 74490

Gnomad4 AFR AF: 0.00178

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00339

Gnomad4 NFE AF: 0.00781

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00635 Hom.: 6

Bravo AF: 0.00436

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00366 AC: 445

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00649

EpiControl AF: 0.00575

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 05, 2019	This variant is associated with the following publications: (PMID: 32442335) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 25, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	LARS2: BS2 -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 06, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Asp518Asn in exon 14 of LARS2: This variant is not expected to have clinical sig nificance because it has been identified in 0.8% (67/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs116826217). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 30, 2017	- -

Inborn mitochondrial myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Kids Research, The Children's Hospital at Westmead

Jul 18, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D;D;.;D;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.016	T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.2	M;M;.;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.5	D;D;D;.;.
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D;D;D;.;.
Sift4G	Uncertain	0.036	D;D;D;.;.
Polyphen		1.0	D;D;D;D;D
Vest4		0.95
MVP		0.72
MPC		0.82
ClinPred		0.028	T
GERP RS		5.5
Varity_R		0.77

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: rs116826217; hg19: chr3-45537795;