5-146120289-G-C

Variant names:

• chr5-146120289-G-C
• rs112894446
• NM_020117.11:c.3325+82C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020117.11(LARS1):​c.3325+82C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000986 in 1,441,170 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (4 hom.)
• Consequence: LARS1 NM_020117.11 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.671
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-146120289-G-C is Benign according to our data. Variant chr5-146120289-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1197032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00535 (815/152242) while in subpopulation AFR AF = 0.0186 (775/41556). AF 95% confidence interval is 0.0176. There are 4 homozygotes in GnomAd4. There are 371 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.3325+82C>G		intron	N/A	NP_064502.9
	LARS1	NM_016460.4		c.3244+82C>G		intron	N/A	NP_057544.2
	LARS1	NM_001317964.2		c.3187+82C>G		intron	N/A	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.3325+82C>G		intron	N/A	ENSP00000377954.2	Q9P2J5-1
	LARS1	ENST00000908002.1		c.3445+82C>G		intron	N/A	ENSP00000578061.1
	LARS1	ENST00000907999.1		c.3418+82C>G		intron	N/A	ENSP00000578058.1

Frequencies

GnomAD3 genomes AF: 0.00535 AC: 814 AN: 152124 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0187

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.000470 AC: 606 AN: 1288928 Hom.: 4 Cov.: 17 AF XY: 0.000416 AC XY: 270 AN XY: 649162

African (AFR) AF: 0.0180 AC: 512 AN: 28440

American (AMR) AF: 0.000885 AC: 32 AN: 36140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24452

East Asian (EAS) AF: 0.00 AC: 0 AN: 38520

South Asian (SAS) AF: 0.0000389 AC: 3 AN: 77168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52526

Middle Eastern (MID) AF: 0.000406 AC: 2 AN: 4924

European-Non Finnish (NFE) AF: 0.00000926 AC: 9 AN: 972414

Other (OTH) AF: 0.000883 AC: 48 AN: 54344

GnomAD4 genome AF: 0.00535 AC: 815 AN: 152242 Hom.: 4 Cov.: 32 AF XY: 0.00498 AC XY: 371 AN XY: 74454

African (AFR) AF: 0.0186 AC: 775 AN: 41556

American (AMR) AF: 0.00216 AC: 33 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000278 Hom.: 0

Bravo AF: 0.00596

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.6
DANN	Benign	0.35
PhyloP100		0.67
Mutation Taster		=100/0	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: rs112894446; hg19: chr5-145499852;