3-45476581-C-G

Variant names:

• chr3-45476581-C-G
• NM_015340.4:c.972C>G
• LARS2 p.His324Gln

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015340.4(LARS2):​c.972C>G​(p.His324Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LARS2 NM_015340.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.424
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06606996).

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.972C>G	p.His324Gln	missense	Exon 10 of 22	NP_056155.1	Q15031
	LARS2	NM_001368263.1		c.972C>G	p.His324Gln	missense	Exon 9 of 21	NP_001355192.1	Q15031

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARS2	ENST00000645846.2	MANE Select	c.972C>G	p.His324Gln	missense	Exon 10 of 22	ENSP00000495093.1	Q15031
	LARS2	ENST00000265537.8	TSL:1	n.972C>G		non_coding_transcript_exon	Exon 10 of 23	ENSP00000265537.4	A0A499FJL2
	LARS2	ENST00000935381.1		c.972C>G	p.His324Gln	missense	Exon 10 of 23	ENSP00000605440.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	14
DANN	Benign	0.82
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.42
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.044
Sift	Benign	0.42	T
Sift4G	Benign	0.66	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.052
Mutation Taster		=99/1	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr3-45518073;