6-87589957-T-C

Position:

chr6-87589957-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_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:8

Conservation

PhyloP100: 1.90

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:

RARS2 (HGNC:):

RARS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

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. Variant chr6-87589957-T-C is described in Lovd as [Pathogenic]. Variant chr6-87589957-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RARS2	NM_020320.5 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/20	ENST00000369536.10	NP_064716.2	Q5T160

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RARS2	ENST00000369536.10 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/20	1	NM_020320.5	ENSP00000358549.5		Q5T160

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

GnomAD3 exomes

AF:

0.000112

AC:

AN:

250932

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135824

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 SAS exome

AF:

0.000327

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

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.000394

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000351

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pontocerebellar hypoplasia type 6

Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Neurology Department of Pediatrics, The Third Affiliated Hospital of Zhengzhou University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 05, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 30, 2020	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2024	Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Observed with a second RARS2 variant in patients with features of aminoacyl-tRNA synthetase deficiency in published literature (PMID: 26083569, 25356970, 26795593); This variant is associated with the following publications: (PMID: 34670123, 34085948, 29434700, 26083569, 25356970, 26795593, 25326635, 31980526, 34426522, 31589614, 34247374, 35571021) -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2024

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

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

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

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.95

gMVP

0.71

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over