NM_020320.5:c.35A>G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PP3PP5_Very_Strong

The NM_020320.5(RARS2):c.35A>G(p.Gln12Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,613,322 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q12E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

RARS2
NM_020320.5 missense, splice_region

Scores

Splicing: ADA: 0.9761

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 3.25

Publications

14 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 links:

ORC3 (HGNC:8489): (origin recognition complex subunit 3) The origin recognition complex (ORC) is a highly conserved six subunits protein complex essential for the initiation of the DNA replication in eukaryotic cells. Studies in yeast demonstrated that ORC binds specifically to origins of replication and serves as a platform for the assembly of additional initiation factors such as Cdc6 and Mcm proteins. The protein encoded by this gene is a subunit of the ORC complex. Studies of a similar gene in Drosophila suggested a possible role of this protein in neuronal proliferation and olfactory memory. Alternatively spliced transcript variants encoding distinct isoforms have been reported for this gene. [provided by RefSeq, Jul 2008]

ORC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 12 uncertain in NM_020320.5

PP3

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

PP5

Variant 6-87589923-T-C is Pathogenic according to our data. Variant chr6-87589923-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 30912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARS2	NM_020320.5 link	c.35A>G	p.Gln12Arg	missense_variant, splice_region_variant	Exon 1 of 20	ENST00000369536.10	NP_064716.2	Q5T160
ORC3	NM_012381.4 link	c.-246T>C		upstream_gene_variant		ENST00000392844.8	NP_036513.2	Q9UBD5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARS2	ENST00000369536.10 link	c.35A>G	p.Gln12Arg	missense_variant, splice_region_variant	Exon 1 of 20	1	NM_020320.5	ENSP00000358549.5		Q5T160
ORC3	ENST00000392844.8 link	c.-246T>C		upstream_gene_variant		1	NM_012381.4	ENSP00000376586.3		Q9UBD5-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000679

AC:

AN:

250478

AF XY:

0.0000590

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000153

AC:

224

AN:

1461162

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

104

AN XY:

726766

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33448

American (AMR)

AF:

0.0000447

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5316

European-Non Finnish (NFE)

AF:

0.000183

AC:

204

AN:

1111946

Other (OTH)

AF:

0.000282

AC:

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41458

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

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:

0.000135

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pontocerebellar hypoplasia type 6

Pathogenic:5

Aug 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aug 28, 2019

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A heterozygous splice site variant was identified, NM_020320.4(RARS2):c.35A>G in exon 1 of 20 of the RARS2 gene (NB: This variant is non-coding in alternative transcripts). RNA analysis shows the variant causes abnormal splicing leading to a frameshift and premature termination codon, NP_064716.2(RARS2):p.(Gln12Argfs*25) (Cassandrini, D. et al. (2013); Rankin, J. et al. (2010)). The variant is predicted to result in loss of normal protein function through nonsense-mediated decay. The variant is present in the gnomAD population database at a frequency of 0.02% (17 heterozygotes, 0 homozygotes) in the non-Finnish European population. It is not present in other subpopulations in gnomAD. It has been previously reported in patients with pontocerebellar hypoplasia type 6 (Cassandrini, D. et al. (2013); Rankin, J. et al. (2010)). In addition, functional studies show RARS2 enzyme activity was severely reduced in the cultured skin fibroblasts of a compound heterozygous patient (Cassandrini, D. et al. (2013)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. -

May 04, 2022

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 18, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:4

Oct 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 10, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3, PM3, PM2 -

Apr 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 12 of the RARS2 protein (p.Gln12Arg). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs147391618, gnomAD 0.02%). This missense change has been observed in individuals with pontocerebellar hypoplasia (PMID: 20635367, 20952379, 22569581). ClinVar contains an entry for this variant (Variation ID: 30912). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Studies have shown that this missense change results in alternative splicing and introduces a premature termination codon (PMID: 20635367, 22569581). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Feb 23, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies found this variant results in abnormal splicing (Rankin J et al., 2010; Cassandrini D et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 30006346, 34426522, 22086604, 27061686, 22569581, 23427196, 20635367, 20952379, 34717047, 35468344, 33972171) -

Inborn genetic diseases

Pathogenic:1

Jan 08, 2025

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.35A>G (p.Q12R) alteration is located in exon 1 (coding exon 1) of the RARS2 gene. This alteration results from a A to G substitution at nucleotide position 35, causing the glutamine (Q) at amino acid position 12 to be replaced by an arginine (R). Based on data from gnomAD, the G allele has an overall frequency of 0.007% (17/250478) total alleles studied. The highest observed frequency was 0.015% (17/113268) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and/or in conjunction with other RARS2 variant(s) in individual(s) with features consistent with mitochondrial arginyl-tRNA synthetase deficiency; in at least one instance, the variants were identified in trans (Rankin, 2010; Namavar, 2011; Cassandrini, 2013; Roux, 2021). This nucleotide position is highly conserved in available vertebrate species. In multiple assays testing RARS2 splicing, this variant showed functionally abnormal results consistent with inclusion of a portion of intron 1, generating a premature stop codon (Rankin, 2010; Cassandrini, 2013).The stop codon in the predicted resulting transcript occurs in the 5' end of the RARS2 gene. As such, this alteration may escape nonsense-mediated mRNA decay and/or be prone to rescue by reinitiation (Rivas, 2015; Lindeboom, 2016; Rhee, 2017). The exact functional effect of this alteration is unknown; however, the region predicted to be impacted is critical for protein function (Ambry internal data). The in silico prediction for this missense alteration is inconclusive. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.031

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.041

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.79

M_CAP

Benign

0.028

MetaRNN

Uncertain

0.45

MetaSVM

Benign

-0.96

MutationAssessor

Benign

2.0

PhyloP100

3.3

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.40

Sift

Benign

0.078

Sift4G

Benign

0.15

Polyphen

0.0

Vest4

0.74

MVP

0.69

MPC

0.12

ClinPred

0.21

GERP RS

4.0

PromoterAI

-0.26

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.18

gMVP

0.61

Mutation Taster

=35/65

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.90

SpliceAI score (max)

0.58

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.58

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over