Variant 3-45485752-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate

The NM_015340.4(LARS2):c.1079T>C(p.Ile360Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LARS2
NM_015340.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 6.88

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 links:

LARS2-AS1 (HGNC:40796): (LARS2 antisense RNA 1)

LARS2-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.82

PP5

Variant 3-45485752-T-C is Pathogenic according to our data. Variant chr3-45485752-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2446359.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARS2	NM_015340.4 linkuse as main transcript	c.1079T>C	p.Ile360Thr	missense_variant	11/22	ENST00000645846.2
LARS2-AS1	NR_048543.1 linkuse as main transcript	n.518-1721A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARS2	ENST00000645846.2 linkuse as main transcript	c.1079T>C	p.Ile360Thr	missense_variant	11/22		NM_015340.4	P1
LARS2-AS1	ENST00000442534.2 linkuse as main transcript	n.518-1721A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459364

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726112

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Perrault syndrome 4

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Precision Medicine Center, Zhengzhou University

This variant was observed in compound heterozygosity with variant NM_015340.4:c.1565C>A in a male patient, and it is absent in gnomAD, and REVEL SCORE >0.644 -

LARS2-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 27, 2024

The LARS2 c.1079T>C variant is predicted to result in the amino acid substitution p.Ile360Thr. This variant has been reported in compound heterozygous state with pathogenic c.1565C>A variant in an individual with Perrault syndrome (Lei et al. 2023. PubMed ID: 38186093). This variant has not been reported in a large population database, indicating this variant is rare. It is documented as likely pathogenic in ClinVar by a single lab, and noted to have been found in compound heterozygosity with the common pathogenic c.1565C>A variant (https://preview.ncbi.nlm.nih.gov/clinvar/variation/2446359/). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;D;.;D;D

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

.;.;D;.;D

M_CAP

Benign

0.027

MetaRNN

Pathogenic

0.82

D;D;D;D;D

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.2

M;M;.;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-4.1

D;D;D;.;.

REVEL

Uncertain

0.37

Sift

Uncertain

0.018

D;D;D;.;.

Sift4G

Uncertain

0.026

D;D;D;.;.

Polyphen

0.77

P;P;P;P;P

Vest4

0.75

MutPred

0.67

Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);.;Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);

MVP

0.73

MPC

0.77

ClinPred

0.99

GERP RS

5.4

Varity_R

0.24

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over