5-146151995-A-T

Position:

chr5-146151995-A-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2

The NM_020117.11(LARS1):c.1292T>A(p.Val431Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00068 in 1,613,958 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00069 ( 2 hom. )

Consequence

LARS1
NM_020117.11 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:6

Conservation

PhyloP100: 9.09

Variant links:

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]

LARS1 links:

LARS1 (HGNC:):

LARS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP5

Variant 5-146151995-A-T is Pathogenic according to our data. Variant chr5-146151995-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 431849.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=6, Pathogenic=3, Likely_pathogenic=4}.

BP4

Computational evidence support a benign effect (MetaRNN=0.27590314). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARS1	NM_020117.11 linkuse as main transcript	c.1292T>A	p.Val431Asp	missense_variant	14/32	ENST00000394434.7	NP_064502.9	Q9P2J5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LARS1	ENST00000394434.7 linkuse as main transcript	c.1292T>A	p.Val431Asp	missense_variant	14/32	1	NM_020117.11	ENSP00000377954.2		Q9P2J5-1

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000764

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000339

AC:

AN:

251104

Hom.:

AF XY:

0.000332

AC XY:

AN XY:

135740

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000605

Gnomad NFE exome

AF:

0.000537

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000692

AC:

1011

AN:

1461644

Hom.:

Cov.:

AF XY:

0.000673

AC XY:

489

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000338

Gnomad4 NFE exome

AF:

0.000843

Gnomad4 OTH exome

AF:

0.000546

GnomAD4 genome

AF:

0.000571

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000764

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000497

Hom.:

Bravo

AF:

0.000914

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000379

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Infantile liver failure syndrome 1

Pathogenic:3Uncertain:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant has been previously reported as a compound heterozygous change in patients with infantile liver failure syndrome 1 (PMID: 30349989, 32699352). Functional studies showed that the presence of the c.1292T>A (p.Val431Asp) variant, with another LARS pathogenic variant in trans, resulted in reduced protein levels (PMID: 32699352, 34194004). The c.1292T>A (p.Val431Asp) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.03% (98/282514), and is absent in the homozygous state. Based on the available evidence, the c.1292T>A (p.Val431Asp) variant is classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 31, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with infantile liver failure syndrome 1 (MIM#615438). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (98 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated LARS1 editing domain (PMID: 30349989, 25051973). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed as compound heterozgous in at least nine individuals with infantile liver failure syndrome 1 (MIM#615438) (ClinVar, PMIDs: 30349989, 34023347, 34194004, 32699352). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Studies on fibroblasts from patients with this variant have shown decreased LARS1 enzyme activity and decreased protein expression (PMIDs: 34194004, 32699352). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	Likely pathogenicity based on finding it twice in our laboratory in trans with another variant in individuals with liver dysfunction, anemia, IUGR, heart defects. Heterozygotes would be expected to be asymptomatic carriers. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	Mar 25, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Aug 22, 2022	- -

not provided

Pathogenic:3Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 08, 2020	This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25326635, 30349989, 34023347, 32699352, 25051973, 34194004, 33726816, 37269902, 36135330, 37432431) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Apr 03, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 11, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LARS protein function. ClinVar contains an entry for this variant (Variation ID: 431849). This missense change has been observed in individuals with acute infantile liver failure (PMID: 30349989, 32699352). This variant is present in population databases (rs150429680, gnomAD 0.06%). This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 431 of the LARS protein (p.Val431Asp). -

LARS1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2023

The LARS1 c.1292T>A variant is predicted to result in the amino acid substitution p.Val431Asp. This variant has been reported in multiple unrelated individuals with infantile liver failure syndrome (Peroutka et al. 2019. PubMed ID: 30349989; Lenz et al. 2020. PubMed ID: 32699352; Hegarty et al. 2021. PubMed ID: 34023347). Although this variant was not examined directly, studies of patient derived fibroblasts, compound heterozygous for this variant and a splice variant (c.1503+3A>G), found decreased aminoacylation activity suggesting this variant impacts protein function (Kok et al. 2021. PubMed ID: 34194004). This variant is reported in 0.056% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-145531558-A-T). This variant is interpreted as likely pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 22, 2023

Variant summary: LARS1 c.1292T>A (p.Val431Asp) results in a non-conservative amino acid change located in the Aminoacyl-tRNA synthetase, class Ia domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 282514 control chromosomes. c.1292T>A has been reported in the literature in individuals affected with Liver Failure Acute Infantile, Type 1. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (pathogenic n=1, likely pathogenic n=2, VUS n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

T;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.28

T;T

MetaSVM

Benign

-0.32

MutationAssessor

Benign

1.7

L;.

PrimateAI

Benign

0.36

PROVEAN

Pathogenic

-6.0

D;D

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.75

P;.

Vest4

0.79

MVP

0.77

MPC

0.67

ClinPred

0.18

GERP RS

5.0

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

Varity_R

0.97

gMVP

0.96

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over