NM_015340.4:c.2181G>T

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.2181G>T(p.Lys727Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00243 in 1,613,668 control chromosomes in the GnomAD database, including 73 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K727E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 30 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 43 hom. )

Consequence

LARS2
NM_015340.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.60

Publications

5 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=0.0028013885).

BP6

Variant 3-45518039-G-T is Benign according to our data. Variant chr3-45518039-G-T is described in ClinVar as Benign. ClinVar VariationId is 226701.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 = 0.0131 (2002/152260) while in subpopulation AFR AF = 0.0458 (1903/41548). AF 95% confidence interval is 0.0441. There are 30 homozygotes in GnomAd4. There are 940 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 30 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.2181G>T	p.Lys727Asn	missense	Exon 18 of 22	NP_056155.1	Q15031
	LARS2	NM_001368263.1		c.2181G>T	p.Lys727Asn	missense	Exon 17 of 21	NP_001355192.1	Q15031

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LARS2	ENST00000645846.2	MANE Select	c.2181G>T	p.Lys727Asn	missense	Exon 18 of 22	ENSP00000495093.1	Q15031
LARS2	ENST00000265537.8	TSL:1	n.*571G>T		non_coding_transcript_exon	Exon 19 of 23	ENSP00000265537.4	A0A499FJL2
LARS2	ENST00000265537.8	TSL:1	n.*571G>T		3_prime_UTR	Exon 19 of 23	ENSP00000265537.4	A0A499FJL2

Frequencies

GnomAD3 genomes

AF:

0.0131

AC:

1995

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0457

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00419

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00338

AC:

847

AN:

250954

AF XY:

0.00245

show subpopulations

Gnomad AFR exome

AF:

0.0462

Gnomad AMR exome

AF:

0.00166

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000247

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00132

AC:

1927

AN:

1461408

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

838

AN XY:

727010

show subpopulations

African (AFR)

AF:

0.0450

AC:

1506

AN:

33446

American (AMR)

AF:

0.00195

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.000104

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000127

AC:

141

AN:

1111704

Other (OTH)

AF:

0.00280

AC:

169

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

159

238

318

397

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.0131

AC:

2002

AN:

152260

Hom.:

Cov.:

AF XY:

0.0126

AC XY:

940

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0458

AC:

1903

AN:

41548

American (AMR)

AF:

0.00412

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68020

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

196

295

393

491

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00486

Hom.:

Bravo

AF:

0.0148

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0452

AC:

199

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00434

AC:

527

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

LARS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.085

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.042

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

3.6

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.63

REVEL

Benign

0.064

Sift

Benign

0.40

Sift4G

Benign

0.31

Polyphen

0.0070

Vest4

0.17

MutPred

0.29

Gain of ubiquitination at K722 (P = 0.0301)

MVP

0.46

MPC

0.30

ClinPred

0.0074

GERP RS

3.5

Varity_R

0.076

Mutation Taster

=97/3

polymorphism

(source)

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

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