rs10988

chr5-146120433-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020117.11(LARS1):c.3263G>A(p.Arg1088Lys) variant causes a missense change. The variant allele was found at a frequency of 0.275 in 1,612,416 control chromosomes in the GnomAD database, including 64,821 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.22 (4845 hom., cov: 32)
  • Exomes 𝑓: 0.28 (59976 hom.)
• Consequence: LARS1 NM_020117.11 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.00

Genes affected

LARS1 (HGNC:6512): (leucyl-tRNA synthetase 1) This gene encodes a cytosolic leucine-tRNA synthetase, a member of the class I aminoacyl-tRNA synthetase family. The encoded enzyme catalyzes the ATP-dependent ligation of L-leucine to tRNA(Leu). It is found in the cytoplasm as part of a multisynthetase complex and interacts with the arginine tRNA synthetase through its C-terminal domain. A mutation in this gene was found in affected individuals with infantile liver failure syndrome 1. Alternatively spliced transcript variants of this gene have been observed. [provided by RefSeq, Dec 2015]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032483041).
• BP6: Variant 5-146120433-C-T is Benign according to our data. Variant chr5-146120433-C-T is described in ClinVar as [Benign]. Clinvar id is 138099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARS1	NM_020117.11	c.3263G>A	p.Arg1088Lys	missense_variant	31/32	ENST00000394434.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARS1	ENST00000394434.7	c.3263G>A	p.Arg1088Lys	missense_variant	31/32	1	NM_020117.11	P4
	ENST00000514002.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34153 AN: 151922 Hom.: 4831 Cov.: 32

Gnomad AFR AF: 0.0612

Gnomad AMI AF: 0.443

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.318

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.290

Gnomad OTH AF: 0.223

GnomAD3 exomes AF: 0.274 AC: 68704 AN: 250466 Hom.: 10920 AF XY: 0.265 AC XY: 35852 AN XY: 135374

Gnomad AFR exome AF: 0.0601

Gnomad AMR exome AF: 0.455

Gnomad ASJ exome AF: 0.170

Gnomad EAS exome AF: 0.219

Gnomad SAS exome AF: 0.175

Gnomad FIN exome AF: 0.313

Gnomad NFE exome AF: 0.288

Gnomad OTH exome AF: 0.269

GnomAD4 exome AF: 0.280 AC: 408891 AN: 1460380 Hom.: 59976 Cov.: 33 AF XY: 0.276 AC XY: 200257 AN XY: 726522

Gnomad4 AFR exome AF: 0.0561

Gnomad4 AMR exome AF: 0.444

Gnomad4 ASJ exome AF: 0.171

Gnomad4 EAS exome AF: 0.224

Gnomad4 SAS exome AF: 0.178

Gnomad4 FIN exome AF: 0.320

Gnomad4 NFE exome AF: 0.293

Gnomad4 OTH exome AF: 0.252

GnomAD4 genome AF: 0.225 AC: 34173 AN: 152036 Hom.: 4845 Cov.: 32 AF XY: 0.225 AC XY: 16748 AN XY: 74296

Gnomad4 AFR AF: 0.0610

Gnomad4 AMR AF: 0.336

Gnomad4 ASJ AF: 0.173

Gnomad4 EAS AF: 0.214

Gnomad4 SAS AF: 0.176

Gnomad4 FIN AF: 0.318

Gnomad4 NFE AF: 0.290

Gnomad4 OTH AF: 0.221

Alfa AF: 0.266 Hom.: 14205

Bravo AF: 0.224

TwinsUK AF: 0.293 AC: 1088

ALSPAC AF: 0.290 AC: 1119

ESP6500AA AF: 0.0679 AC: 299

ESP6500EA AF: 0.279 AC: 2397

ExAC AF: 0.264 AC: 32095

Asia WGS AF: 0.183 AC: 639 AN: 3478

EpiCase AF: 0.264

EpiControl AF: 0.265

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 29, 2013

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0082	T;.;.
Eigen	Benign	-0.0092
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.62	T;T;T
MetaRNN	Benign	0.0032	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;.;.
MutationTaster	Benign	0.000023	P;P;P;P
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.41	N;.;N
REVEL	Benign	0.092
Sift	Benign	0.30	T;.;T
Sift4G	Benign	0.45	T;T;T
Polyphen		0.073	B;.;.
Vest4		0.26
MPC		0.22
ClinPred		0.024	T
GERP RS		4.5
Varity_R		0.20
gMVP		0.74

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: rs10988; hg19: chr5-145499996; COSMIC: COSV50972264; COSMIC: COSV50972264;