rs77377258

Variant names:

• chr3-45394475-T-C
• rs77377258
• NM_015340.4:c.22T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015340.4(LARS2):​c.22T>C​(p.Leu8Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000983 in 1,613,874 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (7 hom.)
• Consequence: LARS2 NM_015340.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.457
• 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 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=-0.81).
• BP6: Variant 3-45394475-T-C is Benign according to our data. Variant chr3-45394475-T-C is described in ClinVar as Benign. ClinVar VariationId is 226702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.457 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00505 (768/152170) while in subpopulation AFR AF = 0.0173 (717/41502). AF 95% confidence interval is 0.0162. There are 8 homozygotes in GnomAd4. There are 358 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.22T>C	p.Leu8Leu	synonymous	Exon 3 of 22	NP_056155.1	Q15031
	LARS2	NM_001368263.1		c.22T>C	p.Leu8Leu	synonymous	Exon 2 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.22T>C	p.Leu8Leu	synonymous	Exon 3 of 22	ENSP00000495093.1	Q15031
	LARS2	ENST00000265537.8	TSL:1	n.22T>C		non_coding_transcript_exon	Exon 3 of 23	ENSP00000265537.4	A0A499FJL2
	LARS2	ENST00000935381.1		c.22T>C	p.Leu8Leu	synonymous	Exon 3 of 23	ENSP00000605440.1

Frequencies

GnomAD3 genomes AF: 0.00506 AC: 770 AN: 152052 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00141 AC: 354 AN: 251406 AF XY: 0.00107

Gnomad AFR exome AF: 0.0185

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000560 AC: 819 AN: 1461704 Hom.: 7 Cov.: 31 AF XY: 0.000535 AC XY: 389 AN XY: 727178

African (AFR) AF: 0.0186 AC: 621 AN: 33474

American (AMR) AF: 0.000872 AC: 39 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86248

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.0000630 AC: 70 AN: 1111846

Other (OTH) AF: 0.00113 AC: 68 AN: 60396

GnomAD4 genome AF: 0.00505 AC: 768 AN: 152170 Hom.: 8 Cov.: 33 AF XY: 0.00481 AC XY: 358 AN XY: 74398

African (AFR) AF: 0.0173 AC: 717 AN: 41502

American (AMR) AF: 0.00151 AC: 23 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68010

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00250 Hom.: 1

Bravo AF: 0.00591

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

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	-0.81
CADD	Benign	10
DANN	Benign	0.67
PhyloP100		0.46
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs77377258; hg19: chr3-45435967;