rs145297855

chr6-87529647-C-Achr6-87529647-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_020320.5(RARS2):c.773G>T(p.Arg258Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000209 in 1,436,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R258H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RARS2 NM_020320.5 missense, splice_region
• Scores: Splicing: ADA: 0.9700
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.75

Genes affected

RARS2 (HGNC:21406): (arginyl-tRNA synthetase 2, mitochondrial) This nuclear gene encodes a protein that localizes to the mitochondria, where it catalyzes the transfer of L-arginine to its cognate tRNA, an important step in translation of mitochondrially-encoded proteins. Defects in this gene are a cause of pontocerebellar hypoplasia type 6 (PCH6). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-87529648-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 215079.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RARS2	NM_020320.5	c.773G>T	p.Arg258Leu	missense_variant, splice_region_variant	10/20	ENST00000369536.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RARS2	ENST00000369536.10	c.773G>T	p.Arg258Leu	missense_variant, splice_region_variant	10/20	1	NM_020320.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1436536 Hom.: 0 Cov.: 26 AF XY: 0.00000279 AC XY: 2 AN XY: 716432

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: 0.00000275

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.60	P
Vest4		0.79
MVP		0.85
MPC		0.31
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.93
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.81
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: rs145297855; hg19: chr6-88239365;