NM_015340.4:c.2547T>C

Variant names:

• chr3-45547365-T-C
• rs78587006
• NM_015340.4:c.2547T>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.2547T>C​(p.Ala849Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,609,898 control chromosomes in the GnomAD database, including 216 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (204 hom.)
• Consequence: LARS2 NM_015340.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.518
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 3-45547365-T-C is Benign according to our data. Variant chr3-45547365-T-C is described in ClinVar as Benign. ClinVar VariationId is 226705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.518 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0722 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.2547T>C	p.Ala849Ala	synonymous	Exon 22 of 22	NP_056155.1
	LARS2	NM_001368263.1		c.2547T>C	p.Ala849Ala	synonymous	Exon 21 of 21	NP_001355192.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARS2	ENST00000645846.2	MANE Select	c.2547T>C	p.Ala849Ala	synonymous	Exon 22 of 22	ENSP00000495093.1
	LARS2	ENST00000265537.8	TSL:1	n.*937T>C		non_coding_transcript_exon	Exon 23 of 23	ENSP00000265537.4
	LARS2	ENST00000265537.8	TSL:1	n.*937T>C		3_prime_UTR	Exon 23 of 23	ENSP00000265537.4

Frequencies

GnomAD3 genomes AF: 0.00314 AC: 478 AN: 152190 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0785

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00616 AC: 1519 AN: 246402 AF XY: 0.00558

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00338

Gnomad EAS exome AF: 0.0784

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00266

GnomAD4 exome AF: 0.00297 AC: 4328 AN: 1457590 Hom.: 204 Cov.: 31 AF XY: 0.00293 AC XY: 2123 AN XY: 725278

African (AFR) AF: 0.0000605 AC: 2 AN: 33082

American (AMR) AF: 0.000184 AC: 8 AN: 43366

Ashkenazi Jewish (ASJ) AF: 0.00413 AC: 107 AN: 25894

East Asian (EAS) AF: 0.0939 AC: 3721 AN: 39634

South Asian (SAS) AF: 0.00202 AC: 173 AN: 85696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5728

European-Non Finnish (NFE) AF: 0.0000837 AC: 93 AN: 1110674

Other (OTH) AF: 0.00369 AC: 222 AN: 60148

GnomAD4 genome AF: 0.00313 AC: 477 AN: 152308 Hom.: 12 Cov.: 32 AF XY: 0.00340 AC XY: 253 AN XY: 74484

African (AFR) AF: 0.000265 AC: 11 AN: 41572

American (AMR) AF: 0.00170 AC: 26 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.0785 AC: 407 AN: 5188

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000487 Hom.: 0

Bravo AF: 0.00313

Asia WGS AF: 0.0240 AC: 83 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000297

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	LARS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.51
PhyloP100		0.52
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: rs78587006; hg19: chr3-45588857;