3-45518027-T-C

Variant names:

• chr3-45518027-T-C
• rs2170549
• NM_015340.4:c.2169T>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.2169T>C​(p.Ala723Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.971 in 1,613,626 control chromosomes in the GnomAD database, including 768,084 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. A723A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.87 (60258 hom., cov: 30)
  • Exomes 𝑓: 0.98 (707826 hom.)
• Consequence: LARS2 NM_015340.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.91
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 3-45518027-T-C is Benign according to our data. Variant chr3-45518027-T-C is described in ClinVar as Benign. ClinVar VariationId is 226700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.91 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.99 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.2169T>C	p.Ala723Ala	synonymous	Exon 18 of 22	NP_056155.1	Q15031
	LARS2	NM_001368263.1		c.2169T>C	p.Ala723Ala	synonymous	Exon 17 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.2169T>C	p.Ala723Ala	synonymous	Exon 18 of 22	ENSP00000495093.1	Q15031
	LARS2	ENST00000265537.8	TSL:1	n.*559T>C		non_coding_transcript_exon	Exon 19 of 23	ENSP00000265537.4	A0A499FJL2
	LARS2	ENST00000265537.8	TSL:1	n.*559T>C		3_prime_UTR	Exon 19 of 23	ENSP00000265537.4	A0A499FJL2

Frequencies

GnomAD3 genomes AF: 0.869 AC: 132104 AN: 151966 Hom.: 60221 Cov.: 30

Gnomad AFR AF: 0.561

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.945

Gnomad ASJ AF: 0.951

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.957

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.953

Gnomad NFE AF: 0.996

Gnomad OTH AF: 0.894

GnomAD2 exomes AF: 0.959 AC: 240782 AN: 251180 AF XY: 0.967

Gnomad AFR exome AF: 0.553

Gnomad AMR exome AF: 0.972

Gnomad ASJ exome AF: 0.949

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.996

Gnomad OTH exome AF: 0.969

GnomAD4 exome AF: 0.982 AC: 1434723 AN: 1461542 Hom.: 707826 Cov.: 38 AF XY: 0.982 AC XY: 714349 AN XY: 727114

African (AFR) AF: 0.545 AC: 18218 AN: 33438

American (AMR) AF: 0.969 AC: 43287 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.949 AC: 24805 AN: 26130

East Asian (EAS) AF: 1.00 AC: 39685 AN: 39694

South Asian (SAS) AF: 0.965 AC: 83228 AN: 86238

European-Finnish (FIN) AF: 1.00 AC: 53412 AN: 53414

Middle Eastern (MID) AF: 0.957 AC: 5514 AN: 5764

European-Non Finnish (NFE) AF: 0.997 AC: 1108563 AN: 1111790

Other (OTH) AF: 0.961 AC: 58011 AN: 60382

GnomAD4 genome AF: 0.869 AC: 132199 AN: 152084 Hom.: 60258 Cov.: 30 AF XY: 0.873 AC XY: 64925 AN XY: 74356

African (AFR) AF: 0.562 AC: 23255 AN: 41408

American (AMR) AF: 0.945 AC: 14450 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.951 AC: 3300 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5168 AN: 5168

South Asian (SAS) AF: 0.957 AC: 4607 AN: 4812

European-Finnish (FIN) AF: 1.00 AC: 10610 AN: 10610

Middle Eastern (MID) AF: 0.952 AC: 280 AN: 294

European-Non Finnish (NFE) AF: 0.996 AC: 67736 AN: 68016

Other (OTH) AF: 0.895 AC: 1881 AN: 2102

Alfa AF: 0.938 Hom.: 46786

Bravo AF: 0.849

Asia WGS AF: 0.957 AC: 3327 AN: 3478

EpiCase AF: 0.994

EpiControl AF: 0.994

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	-0.75
CADD	Benign	1.3
DANN	Benign	0.45
PhyloP100		-1.9
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: rs2170549; hg19: chr3-45559519; COSMIC: COSV55527324;