rs34965084

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015340.4(LARS2):c.2602G>A(p.Glu868Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000525 in 1,613,862 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 2 hom. )

Consequence

LARS2
NM_015340.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.48

Publications

7 publications found

Variant links:

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)

LARS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036411285).

BP6

Variant 3-45547420-G-A is Benign according to our data. Variant chr3-45547420-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 385400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00246 (374/152280) while in subpopulation AFR AF = 0.00785 (326/41548). AF 95% confidence interval is 0.00715. There are 3 homozygotes in GnomAd4. There are 181 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 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.2602G>A	p.Glu868Lys	missense	Exon 22 of 22	NP_056155.1	Q15031
	LARS2	NM_001368263.1		c.2602G>A	p.Glu868Lys	missense	Exon 21 of 21	NP_001355192.1	Q15031

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LARS2	ENST00000645846.2	MANE Select	c.2602G>A	p.Glu868Lys	missense	Exon 22 of 22	ENSP00000495093.1	Q15031
LARS2	ENST00000265537.8	TSL:1	n.*992G>A		non_coding_transcript_exon	Exon 23 of 23	ENSP00000265537.4	A0A499FJL2
LARS2	ENST00000265537.8	TSL:1	n.*992G>A		3_prime_UTR	Exon 23 of 23	ENSP00000265537.4	A0A499FJL2

Frequencies

GnomAD3 genomes

AF:

0.00246

AC:

374

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00787

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.000721

AC:

181

AN:

250966

AF XY:

0.000553

show subpopulations

Gnomad AFR exome

AF:

0.00862

Gnomad AMR exome

AF:

0.000611

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000324

AC:

474

AN:

1461582

Hom.:

Cov.:

AF XY:

0.000325

AC XY:

236

AN XY:

727074

show subpopulations

African (AFR)

AF:

0.00930

AC:

311

AN:

33454

American (AMR)

AF:

0.000694

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39656

South Asian (SAS)

AF:

0.000104

AC:

AN:

86192

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000468

AC:

AN:

1111916

Other (OTH)

AF:

0.000944

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

102

128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00246

AC:

374

AN:

152280

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

181

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00785

AC:

326

AN:

41548

American (AMR)

AF:

0.00157

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68020

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00101

Hom.:

Bravo

AF:

0.00273

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00953

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000906

AC:

110

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

LARS2-related disorder (1)

Perrault syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0036

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

3.5

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.63

REVEL

Benign

0.097

Sift

Benign

0.29

Sift4G

Benign

0.55

Polyphen

0.97

Vest4

0.16

MVP

0.47

MPC

0.25

ClinPred

0.020

GERP RS

2.7

Varity_R

0.028

Mutation Taster

=89/11

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over