rs3821895

Variant names:

• chr3-45546491-A-G
• rs3821895
• NM_015340.4:c.2533-860A>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.2533-860A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 152,220 control chromosomes in the GnomAD database, including 5,906 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 0.27 (5906 hom., cov: 32)
• Consequence: LARS2 NM_015340.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.762
• 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 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LARS2	NM_015340.4	c.2533-860A>G		intron_variant	Intron 21 of 21	ENST00000645846.2	NP_056155.1
LARS2	NM_001368263.1	c.2533-860A>G		intron_variant	Intron 20 of 20		NP_001355192.1
LARS2	XM_017006042.2	c.2405-860A>G		intron_variant	Intron 20 of 20		XP_016861531.1
LARS2	XM_047447830.1	c.2405-860A>G		intron_variant	Intron 19 of 19		XP_047303786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LARS2	ENST00000645846.2	c.2533-860A>G		intron_variant	Intron 21 of 21		NM_015340.4	ENSP00000495093.1

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41303 AN: 152100 Hom.: 5902 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.377

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.398

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.311

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

GnomAD4 genome AF: 0.271 AC: 41316 AN: 152220 Hom.: 5906 Cov.: 32 AF XY: 0.267 AC XY: 19869 AN XY: 74412

African (AFR) AF: 0.215 AC: 8919 AN: 41524

American (AMR) AF: 0.292 AC: 4468 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 1309 AN: 3470

East Asian (EAS) AF: 0.194 AC: 1009 AN: 5190

South Asian (SAS) AF: 0.289 AC: 1395 AN: 4826

European-Finnish (FIN) AF: 0.197 AC: 2090 AN: 10598

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.311 AC: 21176 AN: 67994

Other (OTH) AF: 0.312 AC: 659 AN: 2112

Alfa AF: 0.275 Hom.: 1013

Bravo AF: 0.275

Asia WGS AF: 0.212 AC: 739 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.74
DANN	Benign	0.35
PhyloP100		-0.76
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: rs3821895; hg19: chr3-45587983;