NM_015340.4:c.1983G>A

Variant names:

• chr3-45516215-G-A
• rs11549809
• NM_015340.4:c.1983G>A

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.1983G>A​(p.Thr661Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,613,508 control chromosomes in the GnomAD database, including 72,801 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5876 hom., cov: 32)
  • Exomes 𝑓: 0.30 (66925 hom.)
• Consequence: LARS2 NM_015340.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.78
• Publications: 24 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 3-45516215-G-A is Benign according to our data. Variant chr3-45516215-G-A is described in ClinVar as Benign. ClinVar VariationId is 226698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.78 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.308 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.1983G>A	p.Thr661Thr	synonymous	Exon 17 of 22	NP_056155.1	Q15031
	LARS2	NM_001368263.1		c.1983G>A	p.Thr661Thr	synonymous	Exon 16 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.1983G>A	p.Thr661Thr	synonymous	Exon 17 of 22	ENSP00000495093.1	Q15031
	LARS2	ENST00000265537.8	TSL:1	n.*373G>A		non_coding_transcript_exon	Exon 18 of 23	ENSP00000265537.4	A0A499FJL2
	LARS2	ENST00000265537.8	TSL:1	n.*373G>A		3_prime_UTR	Exon 18 of 23	ENSP00000265537.4	A0A499FJL2

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41129 AN: 151992 Hom.: 5873 Cov.: 32

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.378

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.309

GnomAD2 exomes AF: 0.280 AC: 70237 AN: 251242 AF XY: 0.289

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.206

Gnomad ASJ exome AF: 0.364

Gnomad EAS exome AF: 0.196

Gnomad FIN exome AF: 0.212

Gnomad NFE exome AF: 0.322

Gnomad OTH exome AF: 0.307

GnomAD4 exome AF: 0.299 AC: 436892 AN: 1461398 Hom.: 66925 Cov.: 35 AF XY: 0.301 AC XY: 218640 AN XY: 727012

African (AFR) AF: 0.213 AC: 7138 AN: 33466

American (AMR) AF: 0.213 AC: 9540 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 9469 AN: 26126

East Asian (EAS) AF: 0.204 AC: 8099 AN: 39692

South Asian (SAS) AF: 0.304 AC: 26183 AN: 86202

European-Finnish (FIN) AF: 0.223 AC: 11914 AN: 53418

Middle Eastern (MID) AF: 0.406 AC: 2343 AN: 5766

European-Non Finnish (NFE) AF: 0.310 AC: 344069 AN: 1111648

Other (OTH) AF: 0.300 AC: 18137 AN: 60374

GnomAD4 genome AF: 0.270 AC: 41139 AN: 152110 Hom.: 5876 Cov.: 32 AF XY: 0.266 AC XY: 19787 AN XY: 74330

African (AFR) AF: 0.210 AC: 8732 AN: 41494

American (AMR) AF: 0.293 AC: 4481 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.378 AC: 1310 AN: 3470

East Asian (EAS) AF: 0.194 AC: 1001 AN: 5168

South Asian (SAS) AF: 0.293 AC: 1413 AN: 4818

European-Finnish (FIN) AF: 0.198 AC: 2092 AN: 10584

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

European-Non Finnish (NFE) AF: 0.311 AC: 21162 AN: 67978

Other (OTH) AF: 0.311 AC: 657 AN: 2114

Alfa AF: 0.308 Hom.: 22018

Bravo AF: 0.274

Asia WGS AF: 0.214 AC: 743 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	-0.65
CADD	Benign	0.38
DANN	Benign	0.47
PhyloP100		-1.8
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: rs11549809; hg19: chr3-45557707; COSMIC: COSV55526276; COSMIC: COSV55526276;