rs1553628118

Variant names:

• chr3-45417534-C-T
• rs1553628118
• NM_015340.4:c.416C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_015340.4(LARS2):​c.416C>T​(p.Ala139Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,802 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LARS2 NM_015340.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.40
• 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):

• hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Perrault syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Perrault syndrome 4

  Inheritance: AR Classification: STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962

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.416C>T	p.Ala139Val	missense	Exon 5 of 22	NP_056155.1
	LARS2	NM_001368263.1		c.416C>T	p.Ala139Val	missense	Exon 4 of 21	NP_001355192.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARS2	ENST00000645846.2	MANE Select	c.416C>T	p.Ala139Val	missense	Exon 5 of 22	ENSP00000495093.1
	LARS2	ENST00000265537.8	TSL:1	n.416C>T		non_coding_transcript_exon	Exon 5 of 23	ENSP00000265537.4
	LARS2	ENST00000935381.1		c.416C>T	p.Ala139Val	missense	Exon 5 of 23	ENSP00000605440.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461802 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727198

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111934

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		4.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.98	D
Vest4		0.73
MutPred		0.82		Loss of disorder (P = 0.0796)
MVP		0.91
MPC		0.78
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.88
Mutation Taster		=39/61	disease causing

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

Other links and lift over

dbSNP: rs1553628118; hg19: chr3-45459026;