3-45419670-A-C

Position:

• chr3-45419670-A-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_015340.4(LARS2):​c.457A>C​(p.Asn153His) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LARS2 NM_015340.4 missense, splice_region
• Scores: Splicing: ADA: 0.9259
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• Conservation: PhyloP100: 5.18

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875
• PP5: Variant 3-45419670-A-C is Pathogenic according to our data. Variant chr3-45419670-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45419670-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARS2	NM_015340.4	c.457A>C	p.Asn153His	missense_variant, splice_region_variant	6/22	ENST00000645846.2	NP_056155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LARS2	ENST00000645846.2	c.457A>C	p.Asn153His	missense_variant, splice_region_variant	6/22		NM_015340.4	ENSP00000495093	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Perrault syndrome 4 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Breakthrough Genomics, Breakthrough Genomics	Mar 22, 2021	This variant was previously reported in compound heterozygous state in a 8-year old Perrault syndrome female patient with a clinical presentation of severe sensorineural hearing loss and found to segregate in autosomal recessive pattern in this family was classified as pathogenic [PMID:32423379]. In addition, this variant was reported in homozygous state in 27-year-old female patient presented with deafness since birth and later showed primary amenorrhea with normal hemoglobin levels, kidney, and liver function tests, [PMID:31274036]. -
Likely pathogenic, criteria provided, single submitter	research	King Laboratory, University of Washington	Aug 01, 2020	LARS2 c.457A>C, p.N153H alters a residue of LARS2 completely conserved in all sequenced vertebrates. The variant is homozygous in 8 children from 4 Palestinian families with ovarian dysgenesis in females and hearing loss and progressive neurological problems in both sexes (Abu Rayyan 2020). It is present in 1 of 1300 Palestinian controls, as a heterozygote, and is absent from public databases. It has been reported previously on ClinVar in subjects of Arab ancestry. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jan 29, 2024	- -
Likely pathogenic, flagged submission	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	-	- -

Perrault syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center of Genomic medicine, Geneva, University Hospital of Geneva

Aug 06, 2018

This variant was identified in combination with a second variant in trans in the same gene (LARS2) in a patient with Perrault syndrome -

Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

May 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;D;.;D;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	.;.;D;.;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	4.3	H;H;.;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.8	D;D;D;.;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.010	D;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;.
Polyphen		1.0	D;D;D;D;D
Vest4		0.76
MutPred		0.74		Gain of disorder (P = 0.0536);Gain of disorder (P = 0.0536);.;Gain of disorder (P = 0.0536);Gain of disorder (P = 0.0536);
MVP		0.93
MPC		0.82
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786205560; hg19: chr3-45461162;