rs143389605

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP5

The NM_001350506.2(RARS2):c.-84A>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000574 in 1,613,050 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 1 hom. )

Consequence

RARS2
NM_001350506.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:9

Conservation

PhyloP100: 4.58

Publications

3 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 1 ACMG points.

PP5

Variant 6-87548600-T-C is Pathogenic according to our data. Variant chr6-87548600-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 358237.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001350506.2. 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.442A>G	p.Thr148Ala	missense	Exon 6 of 20	NP_064716.2	Q5T160
RARS2	NM_001350506.2		c.-84A>G		5_prime_UTR_premature_start_codon_gain	Exon 6 of 21	NP_001337435.1	A0A8I5KPZ0
RARS2	NM_001350507.2		c.-84A>G		5_prime_UTR_premature_start_codon_gain	Exon 7 of 21	NP_001337436.1	H0UI22

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RARS2	ENST00000369536.10	TSL:1 MANE Select	c.442A>G	p.Thr148Ala	missense	Exon 6 of 20	ENSP00000358549.5	Q5T160
RARS2	ENST00000451155.2	TSL:3	c.-84A>G		5_prime_UTR_premature_start_codon_gain	Exon 7 of 22	ENSP00000389656.2	H0Y450
RARS2	ENST00000693431.1		c.-84A>G		5_prime_UTR_premature_start_codon_gain	Exon 6 of 21	ENSP00000509147.1	A0A8I5KPZ0

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000548

AC:

137

AN:

250070

AF XY:

0.000547

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00130

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000932

Gnomad NFE exome

AF:

0.000858

Gnomad OTH exome

AF:

0.000657

GnomAD4 exome

AF:

0.000594

AC:

867

AN:

1460704

Hom.:

Cov.:

AF XY:

0.000549

AC XY:

399

AN XY:

726652

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33454

American (AMR)

AF:

0.000157

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.00165

AC:

AN:

26084

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39558

South Asian (SAS)

AF:

0.000696

AC:

AN:

86170

European-Finnish (FIN)

AF:

0.0000752

AC:

AN:

53204

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.000650

AC:

722

AN:

1111482

Other (OTH)

AF:

0.000447

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

122

163

204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.000387

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41580

American (AMR)

AF:

0.000131

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000632

AC:

AN:

68034

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.000615

Hom.:

Bravo

AF:

0.000400

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000626

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000712

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (8)

Pontocerebellar hypoplasia type 6 (6)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.045

MetaRNN

Uncertain

0.45

MetaSVM

Benign

-0.44

MutationAssessor

Benign

1.8

PhyloP100

4.6

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.9

REVEL

Uncertain

0.56

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.82

MVP

0.82

MPC

0.50

ClinPred

0.29

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.87

gMVP

0.87

Mutation Taster

=32/68

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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