6-87589965-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_020320.5(RARS2):c.-8A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00342 in 1,614,218 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (15 hom.)
• Consequence: RARS2 NM_020320.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.228

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-87589965-T-G is Benign according to our data. Variant chr6-87589965-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 138893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00357 (5213/1461866) while in subpopulation NFE AF= 0.00423 (4704/1112010). AF 95% confidence interval is 0.00413. There are 15 homozygotes in gnomad4_exome. There are 2481 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RARS2	NM_020320.5	c.-8A>C		5_prime_UTR_variant	1/20	ENST00000369536.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RARS2	ENST00000369536.10	c.-8A>C		5_prime_UTR_variant	1/20	1	NM_020320.5	P1

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 305 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00342

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00215 AC: 539 AN: 250940 Hom.: 1 AF XY: 0.00225 AC XY: 306 AN XY: 135828

Gnomad AFR exome AF: 0.000809

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00566

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00328

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00357 AC: 5213 AN: 1461866 Hom.: 15 Cov.: 33 AF XY: 0.00341 AC XY: 2481 AN XY: 727236

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00497

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000510

Gnomad4 FIN exome AF: 0.000693

Gnomad4 NFE exome AF: 0.00423

Gnomad4 OTH exome AF: 0.00333

GnomAD4 genome AF: 0.00200 AC: 305 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.00200 AC XY: 149 AN XY: 74510

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00343

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00222 Hom.: 0

Bravo AF: 0.00220

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 05, 2015	- -

Pontocerebellar hypoplasia type 6 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

RARS2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 07, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	7.1
Dann	Benign	0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Other links and lift over

dbSNP: rs28381459; hg19: chr6-88299683;