6-87589957-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PS1_ModeratePP5_Very_Strong

The NM_020320.5(RARS2):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000638 in 1,614,092 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

RARS2
NM_020320.5 start_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 1.90

Publications

8 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 18 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 62 pathogenic variants. Next in-frame start position is after 176 codons. Genomic position: 87545625. Lost 0.303 part of the original CDS.

PS1

Another start lost variant in NM_020320.5 (RARS2) was described as [Pathogenic] in ClinVar as 1070705

PP5

Variant 6-87589957-T-C is Pathogenic according to our data. Variant chr6-87589957-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225026.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.1A>G	p.Met1?	start_lost	Exon 1 of 20	ENST00000369536.10	NP_064716.2	Q5T160
ORC3	NM_012381.4 link	c.-212T>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.1A>G	p.Met1?	start_lost	Exon 1 of 20	1	NM_020320.5	ENSP00000358549.5		Q5T160
ORC3	ENST00000392844.8 link	c.-212T>C		upstream_gene_variant		1	NM_012381.4	ENSP00000376586.3		Q9UBD5-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000112

AC:

AN:

250932

AF XY:

0.000155

show subpopulations

Gnomad AFR exome

AF:

0.0000623

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000793

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000643

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000756

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33480

American (AMR)

AF:

0.000179

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.000394

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000351

AC:

AN:

1112010

Other (OTH)

AF:

0.0000331

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41468

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pontocerebellar hypoplasia type 6

Pathogenic:9

Mar 06, 2021

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PVS1_Moderate+PM3+PP1+PP4 -

Jan 30, 2020

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 03, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This start lost variant affects the translation initiation codon (Met1) and is therefore predicted to result in loss of normal protein function. Loss-of-function variation in RARS2 is an established mechanism of disease (PMID: 17847012, 24047924, 38438854). This variant has been previously reported as a compound heterozygous change in individuals with pontocerebellar hypoplasia (PMID: 26083569, 25356970, 34247374, 35571021). Other variations (c.1A>T, c.3G>A, c.3G>C) at the same amino acid residue (p.Met1) have been previously reported in individuals with pontocerebellar hypoplasia (PMID: 34717047, 33798445, 35468344). The c.1A>G (p.Met1?) variant is present in the heterozygous state in the gnomAD v4 population database at a frequency of 0.006% (103/1614092), and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, c.1A>G (p.Met1?) is classified as Pathogenic. -

Sep 01, 2017

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This initiation codon variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory with another variant in a 13-year-old male with intellectual disability, epilepsy, truncal ataxia, growth retardation. It was also seen once de novo in a 10-month-old female with epilpsy, delays, hypotonia, who also had a de novo pathogenic ATP1A3 variant. Heterozygotes are expected to be asymptomatic carriers. -

Dec 28, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.011%). Predicted Consequence/Location: Start-lost: reinitiation of translation may occur at a downstream alternate start codon but still result in a loss or disruption of normal protein function as there have been pathogenic variants reported upstream of the alternate start codon. Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 26083569). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 26083569). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000225026 /PMID: 26083569). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Neurology Department of Pediatrics, The Third Affiliated Hospital of Zhengzhou University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Aug 11, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed with a second RARS2 variant in patients with features of aminoacyl-tRNA synthetase deficiency in published literature (PMID: 26083569, 25356970, 26795593); Initiation codon variant in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34670123, 34085948, 29434700, 26083569, 25356970, 26795593, 25326635, 31980526, 34426522, 31589614, 34247374, 35571021) -

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects the initiator methionine of the RARS2 mRNA. The next in-frame methionine is located at codon 176. This variant is present in population databases (rs774923951, gnomAD 0.03%). Disruption of the initiator codon has been observed in individual(s) with pontocerebellar hypoplasia (PMID: 26083569). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 225026). This variant disrupts the p.Gln12 amino acid residue in RARS2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20635367, 20952379, 22569581). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Aug 26, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1A>G (p.M1?) alteration is located in coding exon 1 of the RARS2 gene and results from a A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on data from gnomAD, the G allele has an overall frequency of 0.011% (31/282330) total alleles studied. The highest observed frequency was 0.033% (10/30616) of South Asian alleles. This variant has been identified in conjunction with other RARS2 variants in individuals with features consistent with mitochondrial arginyl-tRNA synthetase; in at least one instance, the variants were identified in trans (Farwell, 2015; Lax, 2015; Helbig, 2016; Matricardi, 2019; Weng, 2021; Chuan, 2022; Zhao, 2024). Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.39

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.013

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.39

MetaRNN

Uncertain

0.74

MetaSVM

Benign

-0.83

PhyloP100

1.9

PROVEAN

Benign

-0.43

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0030

Vest4

0.84

MVP

0.73

ClinPred

0.97

GERP RS

4.0

PromoterAI

-0.32

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.95

gMVP

0.71

Mutation Taster

=4/196

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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6-87589957-T-C

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