3-45547438-G-A

Position:

• chr3-45547438-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_015340.4(LARS2):​c.2620G>A​(p.Glu874Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000199 in 1,613,854 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: LARS2 NM_015340.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 4.81

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06568867).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00021 (32/152238) while in subpopulation SAS AF= 0.00145 (7/4820). AF 95% confidence interval is 0.000681. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARS2	NM_015340.4	c.2620G>A	p.Glu874Lys	missense_variant	22/22	ENST00000645846.2	NP_056155.1
LARS2	NM_001368263.1	c.2620G>A	p.Glu874Lys	missense_variant	21/21		NP_001355192.1
LARS2	XM_017006042.2	c.*77G>A		3_prime_UTR_variant	21/21		XP_016861531.1
LARS2	XM_047447830.1	c.*77G>A		3_prime_UTR_variant	20/20		XP_047303786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LARS2	ENST00000645846.2	c.2620G>A	p.Glu874Lys	missense_variant	22/22		NM_015340.4	ENSP00000495093	P1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000267 AC: 67 AN: 250954 Hom.: 0 AF XY: 0.000280 AC XY: 38 AN XY: 135618

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000349

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000687

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000198 AC: 289 AN: 1461616 Hom.: 1 Cov.: 31 AF XY: 0.000215 AC XY: 156 AN XY: 727096

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000708

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000140

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74432

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000269 Hom.: 1

Bravo AF: 0.000212

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000305 AC: 37

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 19, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 874 of the LARS2 protein (p.Glu874Lys). This variant is present in population databases (rs142215302, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with LARS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 228791). 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 13, 2018

The p.Glu874Lys variant in LARS2 has been previously reported in 1 individual wi th hearing loss, gonadal dysgenesis and renal insufficiency. It has also been id entified in 0.068% (21/30554) of South Asian chromosomes by gnomAD (http://gnoma d.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical signi ficance of this variant is uncertain. ACMG/AMP Criteria applied: BP4, PM2_Suppor ting. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2020

The c.2620G>A (p.E874K) alteration is located in exon 22 (coding exon 20) of the LARS2 gene. This alteration results from a G to A substitution at nucleotide position 2620, causing the glutamic acid (E) at amino acid position 874 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Perrault syndrome 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Feb 11, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;D;.;D;D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.86	.;.;D;.;D
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.066	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.9	L;L;.;L;L
MutationTaster	Benign	0.59	N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.3	N;N;D;.;.
REVEL	Benign	0.095
Sift	Benign	0.031	D;D;D;.;.
Sift4G	Uncertain	0.054	T;T;D;.;.
Polyphen		0.91	P;P;P;P;P
Vest4		0.33
MVP		0.52
MPC		0.44
ClinPred		0.074	T
GERP RS		5.6
Varity_R		0.13

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: rs142215302; hg19: chr3-45588930;