rs9825041

Variant names:

• chr3-45434501-A-G
• rs9825041
• NM_015340.4:c.517-12390A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015340.4(LARS2):​c.517-12390A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.836 in 152,226 control chromosomes in the GnomAD database, including 55,551 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.84 (55551 hom., cov: 32)
• Consequence: LARS2 NM_015340.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.625
• Publications: 7 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 Gene-Disease associations (from GenCC):

• hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Perrault syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Perrault syndrome 4

  Inheritance: AR Classification: STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.958 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LARS2	NM_015340.4	c.517-12390A>G		intron_variant	Intron 6 of 21	ENST00000645846.2	NP_056155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LARS2	ENST00000645846.2	c.517-12390A>G		intron_variant	Intron 6 of 21		NM_015340.4	ENSP00000495093.1

Frequencies

GnomAD3 genomes AF: 0.836 AC: 127193 AN: 152108 Hom.: 55524 Cov.: 32

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.986

Gnomad AMR AF: 0.879

Gnomad ASJ AF: 0.954

Gnomad EAS AF: 0.981

Gnomad SAS AF: 0.942

Gnomad FIN AF: 0.975

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.950

Gnomad OTH AF: 0.858

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.836 AC: 127259 AN: 152226 Hom.: 55551 Cov.: 32 AF XY: 0.842 AC XY: 62640 AN XY: 74438

African (AFR) AF: 0.552 AC: 22904 AN: 41476

American (AMR) AF: 0.878 AC: 13439 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.954 AC: 3313 AN: 3472

East Asian (EAS) AF: 0.981 AC: 5081 AN: 5182

South Asian (SAS) AF: 0.942 AC: 4541 AN: 4820

European-Finnish (FIN) AF: 0.975 AC: 10353 AN: 10618

Middle Eastern (MID) AF: 0.881 AC: 259 AN: 294

European-Non Finnish (NFE) AF: 0.950 AC: 64654 AN: 68040

Other (OTH) AF: 0.859 AC: 1816 AN: 2114

Alfa AF: 0.897 Hom.: 13034

Bravo AF: 0.812

Asia WGS AF: 0.932 AC: 3241 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	5.2
DANN	Benign	0.86
PhyloP100		-0.63
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: rs9825041; hg19: chr3-45475993;