5-146120382-C-T

Variant names:

• chr5-146120382-C-T
• rs1751763424
• NM_020117.11:c.3314G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020117.11(LARS1):​c.3314G>A​(p.Arg1105Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000685 in 1,460,782 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1105G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: LARS1 NM_020117.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• infantile liver failure syndrome 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000251556 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020117.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARS1	NM_020117.11	MANE Select	c.3314G>A	p.Arg1105Gln	missense	Exon 31 of 32	NP_064502.9
	LARS1	NM_016460.4		c.3233G>A	p.Arg1078Gln	missense	Exon 30 of 31	NP_057544.2
	LARS1	NM_001317964.2		c.3176G>A	p.Arg1059Gln	missense	Exon 30 of 31	NP_001304893.1	A0A6I8PL42

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARS1	ENST00000394434.7	TSL:1 MANE Select	c.3314G>A	p.Arg1105Gln	missense	Exon 31 of 32	ENSP00000377954.2	Q9P2J5-1
	LARS1	ENST00000908002.1		c.3434G>A	p.Arg1145Gln	missense	Exon 32 of 33	ENSP00000578061.1
	LARS1	ENST00000907999.1		c.3407G>A	p.Arg1136Gln	missense	Exon 32 of 33	ENSP00000578058.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460782 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726664

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111242

Other (OTH) AF: 0.0000166 AC: 1 AN: 60336

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.1
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.17
Sift	Benign	0.15	T
Sift4G	Benign	0.075	T
Polyphen		0.92	P
Vest4		0.66
MutPred		0.22		Loss of MoRF binding (P = 0.093)
MVP		0.63
MPC		0.28
ClinPred		0.91	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.66
Mutation Taster		=60/40	polymorphism

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

Other links and lift over

dbSNP: rs1751763424; hg19: chr5-145499945;