rs952621

Variant names:

• chr3-45435202-G-A
• rs952621
• NM_015340.4:c.517-11689G>A

Variant summary

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

The NM_015340.4(LARS2):​c.517-11689G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 152,094 control chromosomes in the GnomAD database, including 2,088 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 0.16 (2088 hom., cov: 31)
• Consequence: LARS2 NM_015340.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.945
• Publications: 8 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LARS2	NM_015340.4	c.517-11689G>A		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.517-11689G>A		intron_variant	Intron 6 of 21		NM_015340.4	ENSP00000495093.1

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24890 AN: 151976 Hom.: 2085 Cov.: 31

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.195

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

GnomAD4 genome AF: 0.164 AC: 24903 AN: 152094 Hom.: 2088 Cov.: 31 AF XY: 0.162 AC XY: 12009 AN XY: 74352

African (AFR) AF: 0.132 AC: 5489 AN: 41492

American (AMR) AF: 0.183 AC: 2796 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 571 AN: 3466

East Asian (EAS) AF: 0.166 AC: 858 AN: 5168

South Asian (SAS) AF: 0.142 AC: 682 AN: 4806

European-Finnish (FIN) AF: 0.124 AC: 1310 AN: 10604

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.186 AC: 12625 AN: 67962

Other (OTH) AF: 0.194 AC: 410 AN: 2112

Alfa AF: 0.183 Hom.: 10282

Bravo AF: 0.167

Asia WGS AF: 0.143 AC: 497 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.7
DANN	Benign	0.57
PhyloP100		-0.94
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: rs952621; hg19: chr3-45476694;