3-45524062-A-G

Variant names:

• chr3-45524062-A-G
• rs267220
• NM_015340.4:c.2358A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_015340.4(LARS2):​c.2358A>G​(p.Val786Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.976 in 1,613,866 control chromosomes in the GnomAD database, including 773,893 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (61659 hom., cov: 30)
  • Exomes 𝑓: 0.99 (712234 hom.)
• Consequence: LARS2 NM_015340.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.552
• Publications: 19 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):

• Perrault syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Perrault syndrome 4

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 3-45524062-A-G is Benign according to our data. Variant chr3-45524062-A-G is described in ClinVar as Benign. ClinVar VariationId is 226704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.552 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.991 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARS2	NM_015340.4	MANE Select	c.2358A>G	p.Val786Val	synonymous	Exon 20 of 22	NP_056155.1	Q15031
	LARS2	NM_001368263.1		c.2358A>G	p.Val786Val	synonymous	Exon 19 of 21	NP_001355192.1	Q15031

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARS2	ENST00000645846.2	MANE Select	c.2358A>G	p.Val786Val	synonymous	Exon 20 of 22	ENSP00000495093.1	Q15031
	LARS2	ENST00000265537.8	TSL:1	n.*748A>G		non_coding_transcript_exon	Exon 21 of 23	ENSP00000265537.4	A0A499FJL2
	LARS2	ENST00000265537.8	TSL:1	n.*748A>G		3_prime_UTR	Exon 21 of 23	ENSP00000265537.4	A0A499FJL2

Frequencies

GnomAD3 genomes AF: 0.883 AC: 134263 AN: 152002 Hom.: 61622 Cov.: 30

Gnomad AFR AF: 0.602

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.952

Gnomad ASJ AF: 0.997

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.958

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.968

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.909

GnomAD2 exomes AF: 0.965 AC: 242562 AN: 251454 AF XY: 0.972

Gnomad AFR exome AF: 0.592

Gnomad AMR exome AF: 0.977

Gnomad ASJ exome AF: 0.996

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.977

GnomAD4 exome AF: 0.985 AC: 1440007 AN: 1461746 Hom.: 712234 Cov.: 42 AF XY: 0.986 AC XY: 716874 AN XY: 727180

African (AFR) AF: 0.589 AC: 19696 AN: 33454

American (AMR) AF: 0.973 AC: 43519 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.995 AC: 26013 AN: 26134

East Asian (EAS) AF: 1.00 AC: 39690 AN: 39698

South Asian (SAS) AF: 0.965 AC: 83264 AN: 86256

European-Finnish (FIN) AF: 1.00 AC: 53418 AN: 53420

Middle Eastern (MID) AF: 0.972 AC: 5605 AN: 5768

European-Non Finnish (NFE) AF: 0.999 AC: 1110277 AN: 1111910

Other (OTH) AF: 0.969 AC: 58525 AN: 60388

GnomAD4 genome AF: 0.883 AC: 134359 AN: 152120 Hom.: 61659 Cov.: 30 AF XY: 0.887 AC XY: 65972 AN XY: 74378

African (AFR) AF: 0.603 AC: 24948 AN: 41398

American (AMR) AF: 0.952 AC: 14547 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.997 AC: 3461 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5166 AN: 5166

South Asian (SAS) AF: 0.958 AC: 4625 AN: 4828

European-Finnish (FIN) AF: 1.00 AC: 10616 AN: 10616

Middle Eastern (MID) AF: 0.969 AC: 285 AN: 294

European-Non Finnish (NFE) AF: 0.998 AC: 67880 AN: 68042

Other (OTH) AF: 0.910 AC: 1919 AN: 2108

Alfa AF: 0.944 Hom.: 38818

Bravo AF: 0.865

Asia WGS AF: 0.958 AC: 3332 AN: 3478

EpiCase AF: 0.997

EpiControl AF: 0.997

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	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	-0.43
CADD	Benign	5.6
DANN	Benign	0.78
PhyloP100		0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs267220; hg19: chr3-45565554; COSMIC: COSV108100757;