chr3-45417489-A-T

Position:

• chr3-45417489-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_015340.4(LARS2):​c.371A>T​(p.Asn124Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,520 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LARS2 NM_015340.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.67

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-45417489-A-T is Pathogenic according to our data. Variant chr3-45417489-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 431125.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARS2	NM_015340.4	c.371A>T	p.Asn124Ile	missense_variant	5/22	ENST00000645846.2	NP_056155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LARS2	ENST00000645846.2	c.371A>T	p.Asn124Ile	missense_variant	5/22		NM_015340.4	ENSP00000495093.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461520 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727096

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Perrault syndrome 4 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris	Jan 06, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;D;.;D;D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	.;.;D;.;D
M_CAP	Uncertain	0.087	D
MetaRNN	Uncertain	0.56	D;D;D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.6	M;M;.;M;M
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.7	D;D;D;.;.
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D;D;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;.;.
Polyphen		0.67	P;P;P;P;P
Vest4		0.74
MutPred		0.56		Gain of MoRF binding (P = 0.1041);Gain of MoRF binding (P = 0.1041);.;Gain of MoRF binding (P = 0.1041);Gain of MoRF binding (P = 0.1041);
MVP		0.85
MPC		0.65
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.93

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

LitVar

Other links and lift over

dbSNP: rs776171893; hg19: chr3-45458981;