chr3-45500591-T-C

Variant names:

• chr3-45500591-T-C
• rs2306522
• NM_015340.4:c.1760+12T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015340.4(LARS2):​c.1760+12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.621 in 1,539,344 control chromosomes in the GnomAD database, including 307,286 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (24080 hom., cov: 33)
  • Exomes 𝑓: 0.63 (283206 hom.)
• Consequence: LARS2 NM_015340.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.62
• Publications: 14 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-45500591-T-C is Benign according to our data. Variant chr3-45500591-T-C is described in ClinVar as Benign. ClinVar VariationId is 226697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.76 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARS2	NM_015340.4	MANE Select	c.1760+12T>C		intron	N/A	NP_056155.1
	LARS2	NM_001368263.1		c.1760+12T>C		intron	N/A	NP_001355192.1
	LARS2-AS1	NR_048543.1		n.261-5091A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARS2	ENST00000645846.2	MANE Select	c.1760+12T>C		intron	N/A	ENSP00000495093.1
	LARS2	ENST00000265537.8	TSL:1	n.*150+12T>C		intron	N/A	ENSP00000265537.4
	LARS2	ENST00000935381.1		c.1862+12T>C		intron	N/A	ENSP00000605440.1

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78278 AN: 152032 Hom.: 24071 Cov.: 33

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.795

Gnomad AMR AF: 0.606

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.780

Gnomad SAS AF: 0.557

Gnomad FIN AF: 0.778

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.637

Gnomad OTH AF: 0.504

GnomAD2 exomes AF: 0.625 AC: 119615 AN: 191354 AF XY: 0.624

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.748

Gnomad ASJ exome AF: 0.535

Gnomad EAS exome AF: 0.784

Gnomad FIN exome AF: 0.762

Gnomad NFE exome AF: 0.630

Gnomad OTH exome AF: 0.617

GnomAD4 exome AF: 0.633 AC: 877652 AN: 1387194 Hom.: 283206 Cov.: 30 AF XY: 0.631 AC XY: 434267 AN XY: 688272

African (AFR) AF: 0.145 AC: 4081 AN: 28226

American (AMR) AF: 0.720 AC: 19570 AN: 27172

Ashkenazi Jewish (ASJ) AF: 0.523 AC: 12506 AN: 23910

East Asian (EAS) AF: 0.773 AC: 27612 AN: 35722

South Asian (SAS) AF: 0.566 AC: 42150 AN: 74504

European-Finnish (FIN) AF: 0.749 AC: 39429 AN: 52666

Middle Eastern (MID) AF: 0.473 AC: 2628 AN: 5558

European-Non Finnish (NFE) AF: 0.642 AC: 695117 AN: 1082142

Other (OTH) AF: 0.603 AC: 34559 AN: 57294

GnomAD4 genome AF: 0.515 AC: 78297 AN: 152150 Hom.: 24080 Cov.: 33 AF XY: 0.524 AC XY: 38987 AN XY: 74370

African (AFR) AF: 0.170 AC: 7064 AN: 41510

American (AMR) AF: 0.607 AC: 9266 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.512 AC: 1777 AN: 3470

East Asian (EAS) AF: 0.780 AC: 4038 AN: 5178

South Asian (SAS) AF: 0.557 AC: 2685 AN: 4822

European-Finnish (FIN) AF: 0.778 AC: 8243 AN: 10592

Middle Eastern (MID) AF: 0.466 AC: 136 AN: 292

European-Non Finnish (NFE) AF: 0.637 AC: 43303 AN: 67994

Other (OTH) AF: 0.502 AC: 1060 AN: 2110

Alfa AF: 0.559 Hom.: 9054

Bravo AF: 0.488

Asia WGS AF: 0.657 AC: 2284 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome (1)
-	-	1	Perrault syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.028
DANN	Benign	0.58
PhyloP100		-3.6
Mutation Taster		=100/0	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: rs2306522; hg19: chr3-45542083;