NM_020117.11:c.3263G>A

Variant names:

• chr5-146120433-C-T
• rs10988
• NM_020117.11:c.3263G>A

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 48 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: Benign. The variant received -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 VariationId 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.

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.3263G>A	p.Arg1088Lys	missense	Exon 31 of 32	NP_064502.9
	LARS1	NM_016460.4		c.3182G>A	p.Arg1061Lys	missense	Exon 30 of 31	NP_057544.2
	LARS1	NM_001317964.2		c.3125G>A	p.Arg1042Lys	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.3263G>A	p.Arg1088Lys	missense	Exon 31 of 32	ENSP00000377954.2	Q9P2J5-1
	LARS1	ENST00000908002.1		c.3383G>A	p.Arg1128Lys	missense	Exon 32 of 33	ENSP00000578061.1
	LARS1	ENST00000907999.1		c.3356G>A	p.Arg1119Lys	missense	Exon 32 of 33	ENSP00000578058.1

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

GnomAD2 exomes AF: 0.274 AC: 68704 AN: 250466 AF XY: 0.265

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 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

African (AFR) AF: 0.0561 AC: 1876 AN: 33420

American (AMR) AF: 0.444 AC: 19788 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 4467 AN: 26104

East Asian (EAS) AF: 0.224 AC: 8891 AN: 39648

South Asian (SAS) AF: 0.178 AC: 15301 AN: 86120

European-Finnish (FIN) AF: 0.320 AC: 17062 AN: 53398

Middle Eastern (MID) AF: 0.132 AC: 762 AN: 5758

European-Non Finnish (NFE) AF: 0.293 AC: 325538 AN: 1111052

Other (OTH) AF: 0.252 AC: 15206 AN: 60334

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

African (AFR) AF: 0.0610 AC: 2532 AN: 41512

American (AMR) AF: 0.336 AC: 5123 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 599 AN: 3472

East Asian (EAS) AF: 0.214 AC: 1107 AN: 5162

South Asian (SAS) AF: 0.176 AC: 848 AN: 4822

European-Finnish (FIN) AF: 0.318 AC: 3357 AN: 10558

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.290 AC: 19704 AN: 67944

Other (OTH) AF: 0.221 AC: 466 AN: 2106

Alfa AF: 0.259 Hom.: 18939

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.0
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.092
Sift	Benign	0.30	T
Sift4G	Benign	0.45	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
Mutation Taster		=95/5	polymorphism (auto)

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