rs145297855

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM5PP3PP5

The NM_020320.5(RARS2):c.773G>A(p.Arg258His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000476 in 1,588,752 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R258C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 0 hom. )

Consequence

RARS2
NM_020320.5 missense, splice_region

Scores

Splicing: ADA: 0.9777

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:4

Conservation

PhyloP100: 5.75

Publications

11 publications found

Variant links:

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]

RARS2 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
pontocerebellar hypoplasia type 6
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Laboratory for Molecular Medicine, Ambry Genetics
complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

RARS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-87529648-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 215079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 6-87529647-C-T is Pathogenic according to our data. Variant chr6-87529647-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215080.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020320.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RARS2	NM_020320.5	MANE Select	c.773G>A	p.Arg258His	missense splice_region	Exon 10 of 20	NP_064716.2	Q5T160
RARS2	NM_001350505.2		c.773G>A	p.Arg258His	missense splice_region	Exon 10 of 21	NP_001337434.1	A0A8I5KWC6
RARS2	NM_001350506.2		c.248G>A	p.Arg83His	missense splice_region	Exon 10 of 21	NP_001337435.1	A0A8I5KPZ0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RARS2	ENST00000369536.10	TSL:1 MANE Select	c.773G>A	p.Arg258His	missense splice_region	Exon 10 of 20	ENSP00000358549.5	Q5T160
RARS2	ENST00000687437.1		c.773G>A	p.Arg258His	missense splice_region	Exon 10 of 21	ENSP00000508968.1	A0A8I5KP51
RARS2	ENST00000691725.1		c.773G>A	p.Arg258His	missense splice_region	Exon 10 of 21	ENSP00000509453.1	A0A8I5KWC6

Frequencies

GnomAD3 genomes

AF:

0.000414

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000280

AC:

AN:

250136

AF XY:

0.000236

show subpopulations

Gnomad AFR exome

AF:

0.0000634

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00171

Gnomad NFE exome

AF:

0.000248

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000482

AC:

693

AN:

1436520

Hom.:

Cov.:

AF XY:

0.000448

AC XY:

321

AN XY:

716420

show subpopulations

African (AFR)

AF:

0.000122

AC:

AN:

32916

American (AMR)

AF:

0.0000224

AC:

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25982

East Asian (EAS)

AF:

0.0000506

AC:

AN:

39514

South Asian (SAS)

AF:

0.0000467

AC:

AN:

85706

European-Finnish (FIN)

AF:

0.00156

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.000531

AC:

578

AN:

1089040

Other (OTH)

AF:

0.000352

AC:

AN:

59608

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

104

130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000414

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0000723

AC:

AN:

41516

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00226

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000280

Hom.:

Bravo

AF:

0.000242

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Pontocerebellar hypoplasia type 6 (5)

not provided (4)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.033

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.34

MetaRNN

Uncertain

0.62

MetaSVM

Uncertain

0.41

MutationAssessor

Pathogenic

3.8

PhyloP100

5.8

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-4.6

REVEL

Uncertain

0.49

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.87

MVP

0.94

MPC

0.59

ClinPred

0.91

GERP RS

5.5

Varity_R

0.97

gMVP

0.74

Mutation Taster

=25/75

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.82

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over