3-45485726-T-C

Variant names:

• chr3-45485726-T-C
• rs7610357
• NM_015340.4:c.1053T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015340.4(LARS2):​c.1053T>C​(p.Leu351Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.922 in 1,610,528 control chromosomes in the GnomAD database, including 695,764 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L351L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.80 (52820 hom., cov: 32)
  • Exomes 𝑓: 0.94 (642944 hom.)
• Consequence: LARS2 NM_015340.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0250
• Publications: 26 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 3-45485726-T-C is Benign according to our data. Variant chr3-45485726-T-C is described in ClinVar as Benign. ClinVar VariationId is 226691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.025 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.953 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.1053T>C	p.Leu351Leu	synonymous	Exon 11 of 22	NP_056155.1	Q15031
	LARS2	NM_001368263.1		c.1053T>C	p.Leu351Leu	synonymous	Exon 10 of 21	NP_001355192.1	Q15031
	LARS2-AS1	NR_048543.1		n.518-1695A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARS2	ENST00000645846.2	MANE Select	c.1053T>C	p.Leu351Leu	synonymous	Exon 11 of 22	ENSP00000495093.1	Q15031
	LARS2	ENST00000265537.8	TSL:1	n.1053T>C		non_coding_transcript_exon	Exon 11 of 23	ENSP00000265537.4	A0A499FJL2
	LARS2	ENST00000935381.1		c.1053T>C	p.Leu351Leu	synonymous	Exon 11 of 23	ENSP00000605440.1

Frequencies

GnomAD3 genomes AF: 0.800 AC: 121588 AN: 152062 Hom.: 52803 Cov.: 32

Gnomad AFR AF: 0.422

Gnomad AMI AF: 0.986

Gnomad AMR AF: 0.905

Gnomad ASJ AF: 0.889

Gnomad EAS AF: 0.976

Gnomad SAS AF: 0.921

Gnomad FIN AF: 0.976

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.948

Gnomad OTH AF: 0.826

GnomAD2 exomes AF: 0.912 AC: 227498 AN: 249454 AF XY: 0.921

Gnomad AFR exome AF: 0.413

Gnomad AMR exome AF: 0.946

Gnomad ASJ exome AF: 0.885

Gnomad EAS exome AF: 0.978

Gnomad FIN exome AF: 0.973

Gnomad NFE exome AF: 0.948

Gnomad OTH exome AF: 0.919

GnomAD4 exome AF: 0.935 AC: 1363611 AN: 1458348 Hom.: 642944 Cov.: 34 AF XY: 0.936 AC XY: 679546 AN XY: 725746

African (AFR) AF: 0.402 AC: 13418 AN: 33348

American (AMR) AF: 0.940 AC: 41305 AN: 43938

Ashkenazi Jewish (ASJ) AF: 0.882 AC: 23002 AN: 26076

East Asian (EAS) AF: 0.977 AC: 38630 AN: 39520

South Asian (SAS) AF: 0.929 AC: 79721 AN: 85790

European-Finnish (FIN) AF: 0.971 AC: 51825 AN: 53380

Middle Eastern (MID) AF: 0.885 AC: 5098 AN: 5758

European-Non Finnish (NFE) AF: 0.951 AC: 1055935 AN: 1110322

Other (OTH) AF: 0.908 AC: 54677 AN: 60216

GnomAD4 genome AF: 0.799 AC: 121638 AN: 152180 Hom.: 52820 Cov.: 32 AF XY: 0.806 AC XY: 59943 AN XY: 74412

African (AFR) AF: 0.422 AC: 17482 AN: 41462

American (AMR) AF: 0.905 AC: 13826 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.889 AC: 3088 AN: 3472

East Asian (EAS) AF: 0.976 AC: 5055 AN: 5180

South Asian (SAS) AF: 0.921 AC: 4437 AN: 4820

European-Finnish (FIN) AF: 0.976 AC: 10365 AN: 10622

Middle Eastern (MID) AF: 0.864 AC: 254 AN: 294

European-Non Finnish (NFE) AF: 0.948 AC: 64488 AN: 68030

Other (OTH) AF: 0.827 AC: 1744 AN: 2108

Alfa AF: 0.873 Hom.: 32186

Bravo AF: 0.775

Asia WGS AF: 0.915 AC: 3182 AN: 3478

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	-0.52
CADD	Benign	9.5
DANN	Benign	0.77
PhyloP100		-0.025
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs7610357; hg19: chr3-45527218; COSMIC: COSV108100652;