NM_015340.4:c.1692C>T

Variant names:

• chr3-45500511-C-T
• rs149911756
• NM_015340.4:c.1692C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_015340.4(LARS2):​c.1692C>T​(p.Ala564Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,590,548 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A564A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (7 hom.)
• Consequence: LARS2 NM_015340.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.35
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 3-45500511-C-T is Benign according to our data. Variant chr3-45500511-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.35 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00196 (299/152250) while in subpopulation NFE AF = 0.00329 (224/68020). AF 95% confidence interval is 0.00294. There are 2 homozygotes in GnomAd4. There are 146 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.1692C>T	p.Ala564Ala	synonymous	Exon 15 of 22	NP_056155.1	Q15031
	LARS2	NM_001368263.1		c.1692C>T	p.Ala564Ala	synonymous	Exon 14 of 21	NP_001355192.1	Q15031
	LARS2-AS1	NR_048543.1		n.261-5011G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARS2	ENST00000645846.2	MANE Select	c.1692C>T	p.Ala564Ala	synonymous	Exon 15 of 22	ENSP00000495093.1	Q15031
	LARS2	ENST00000265537.8	TSL:1	n.*82C>T		non_coding_transcript_exon	Exon 16 of 23	ENSP00000265537.4	A0A499FJL2
	LARS2	ENST00000265537.8	TSL:1	n.*82C>T		3_prime_UTR	Exon 16 of 23	ENSP00000265537.4	A0A499FJL2

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 300 AN: 152132 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00329

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00209 AC: 480 AN: 229582 AF XY: 0.00217

Gnomad AFR exome AF: 0.000203

Gnomad AMR exome AF: 0.00144

Gnomad ASJ exome AF: 0.000826

Gnomad EAS exome AF: 0.0000616

Gnomad FIN exome AF: 0.000795

Gnomad NFE exome AF: 0.00334

Gnomad OTH exome AF: 0.00239

GnomAD4 exome AF: 0.00264 AC: 3799 AN: 1438298 Hom.: 7 Cov.: 30 AF XY: 0.00265 AC XY: 1893 AN XY: 715050

African (AFR) AF: 0.000219 AC: 7 AN: 31916

American (AMR) AF: 0.00126 AC: 50 AN: 39568

Ashkenazi Jewish (ASJ) AF: 0.00167 AC: 43 AN: 25766

East Asian (EAS) AF: 0.00 AC: 0 AN: 38042

South Asian (SAS) AF: 0.00146 AC: 119 AN: 81420

European-Finnish (FIN) AF: 0.000544 AC: 29 AN: 53262

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5736

European-Non Finnish (NFE) AF: 0.00308 AC: 3397 AN: 1103084

Other (OTH) AF: 0.00249 AC: 148 AN: 59504

GnomAD4 genome AF: 0.00196 AC: 299 AN: 152250 Hom.: 2 Cov.: 33 AF XY: 0.00196 AC XY: 146 AN XY: 74432

African (AFR) AF: 0.000457 AC: 19 AN: 41558

American (AMR) AF: 0.00288 AC: 44 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00329 AC: 224 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.00305 Hom.: 0

Bravo AF: 0.00186

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	LARS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	1.1
DANN	Benign	0.78
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=93/7	polymorphism

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: rs149911756; hg19: chr3-45542003; COSMIC: COSV55529220; COSMIC: COSV55529220;