rs781382275

Variant names:

• chr3-45520282-A-G
• rs781382275
• NM_015340.4:c.2278A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_015340.4(LARS2):​c.2278A>G​(p.Ser760Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,613,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: LARS2 NM_015340.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.49
• 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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27118248).

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.2278A>G	p.Ser760Gly	missense	Exon 19 of 22	NP_056155.1	Q15031
	LARS2	NM_001368263.1		c.2278A>G	p.Ser760Gly	missense	Exon 18 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.2278A>G	p.Ser760Gly	missense	Exon 19 of 22	ENSP00000495093.1	Q15031
	LARS2	ENST00000265537.8	TSL:1	n.*668A>G		non_coding_transcript_exon	Exon 20 of 23	ENSP00000265537.4	A0A499FJL2
	LARS2	ENST00000265537.8	TSL:1	n.*668A>G		3_prime_UTR	Exon 20 of 23	ENSP00000265537.4	A0A499FJL2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000716 AC: 18 AN: 251408 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1460940 Hom.: 0 Cov.: 29 AF XY: 0.00000826 AC XY: 6 AN XY: 726830

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.000447 AC: 20 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111162

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.000131 AC: 2 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		5.5
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.17
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.72	P
Vest4		0.38
MutPred		0.57		Loss of disorder (P = 0.0853)
MVP		0.52
MPC		0.43
ClinPred		0.33	T
GERP RS		5.9
Varity_R		0.51
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		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: rs781382275; hg19: chr3-45561774;