3-45485724-C-T

Position:

• chr3-45485724-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015340.4(LARS2):​c.1051C>T​(p.Leu351Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L351L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LARS2 NM_015340.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14248347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARS2	NM_015340.4	c.1051C>T	p.Leu351Phe	missense_variant	11/22	ENST00000645846.2
LARS2-AS1	NR_048543.1	n.518-1693G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARS2	ENST00000645846.2	c.1051C>T	p.Leu351Phe	missense_variant	11/22		NM_015340.4	P1
LARS2-AS1	ENST00000442534.2	n.518-1693G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458840 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 725912

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 11, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with LARS2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 351 of the LARS2 protein (p.Leu351Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T;T;.;T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.010
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.85	.;.;T;.;T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N;N;.;N;N
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	1.9	N;N;N;.;.
REVEL	Benign	0.039
Sift	Benign	0.97	T;T;T;.;.
Sift4G	Benign	1.0	T;T;T;.;.
Polyphen		0.0070	B;B;B;B;B
Vest4		0.14
MutPred		0.58		Loss of helix (P = 0.0123);Loss of helix (P = 0.0123);.;Loss of helix (P = 0.0123);Loss of helix (P = 0.0123);
MVP		0.46
MPC		0.26
ClinPred		0.88	D
GERP RS		4.3
Varity_R		0.069

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-45527216;