NM_015340.4:c.1115C>G

Variant names:

• chr3-45485788-C-G
• rs1559484149
• NM_015340.4:c.1115C>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_015340.4(LARS2):​c.1115C>G​(p.Ser372*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LARS2 NM_015340.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.12
• Publications: 0 publications found

Genes affected

LARS2 (HGNC:17095): (leucyl-tRNA synthetase 2, mitochondrial) This gene encodes a class 1 aminoacyl-tRNA synthetase, mitochondrial leucyl-tRNA synthetase. Each of the twenty aminoacyl-tRNA synthetases catalyzes the aminoacylation of a specific tRNA or tRNA isoaccepting family with the cognate amino acid. [provided by RefSeq, Jul 2008]

LARS2-AS1 (HGNC:40796): (LARS2 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-45485788-C-G is Pathogenic according to our data. Variant chr3-45485788-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 623147.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015340.4. 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
	LARS2	NM_015340.4	MANE Select	c.1115C>G	p.Ser372*	stop_gained	Exon 11 of 22	NP_056155.1	Q15031
	LARS2	NM_001368263.1		c.1115C>G	p.Ser372*	stop_gained	Exon 10 of 21	NP_001355192.1	Q15031
	LARS2-AS1	NR_048543.1		n.518-1757G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARS2	ENST00000645846.2	MANE Select	c.1115C>G	p.Ser372*	stop_gained	Exon 11 of 22	ENSP00000495093.1	Q15031
	LARS2	ENST00000265537.8	TSL:1	n.1115C>G		non_coding_transcript_exon	Exon 11 of 23	ENSP00000265537.4	A0A499FJL2
	LARS2	ENST00000935381.1		c.1115C>G	p.Ser372*	stop_gained	Exon 11 of 23	ENSP00000605440.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Perrault syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		5.1
Vest4		0.39
GERP RS		5.4
Mutation Taster		=5/195	disease causing (ClinVar)

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: rs1559484149; hg19: chr3-45527280;