Variant 5-146120385-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020117.11(LARS1):c.3311A>G(p.Asn1104Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000527 in 1,613,248 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 1 hom. )

Consequence

LARS1
NM_020117.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.15

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.034154415).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARS1	NM_020117.11 linkuse as main transcript	c.3311A>G	p.Asn1104Ser	missense_variant	31/32	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.3311A>G	p.Asn1104Ser	missense_variant	31/32	1	NM_020117.11	ENSP00000377954.2		Q9P2J5-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000797

AC:

AN:

251046

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135680

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000513

AC:

AN:

1460932

Hom.:

Cov.:

AF XY:

0.0000826

AC XY:

AN XY:

726748

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.000661

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.000115

AC:

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2022

The c.3311A>G (p.N1104S) alteration is located in exon 31 (coding exon 31) of the LARS gene. This alteration results from a A to G substitution at nucleotide position 3311, causing the asparagine (N) at amino acid position 1104 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0043

T;.;.

Eigen

Benign

-0.076

Eigen_PC

Benign

0.13

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.034

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.3

L;.;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.52

N;.;N

REVEL

Benign

0.068

Sift

Benign

0.45

T;.;T

Sift4G

Benign

0.42

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.094

MutPred

0.24

Gain of phosphorylation at N1104 (P = 0.0132);.;.;

MVP

0.55

MPC

0.17

ClinPred

0.082

GERP RS

5.3

Varity_R

0.083

gMVP

0.39

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