6-87514172-G-A

Variant names:

• chr6-87514172-G-A
• rs35706399
• NM_020320.5:c.*241C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_020320.5(RARS2):​c.*241C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0905 in 152,050 control chromosomes in the GnomAD database, including 664 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.090 (664 hom., cov: 31)
• Consequence: RARS2 NM_020320.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.252
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 6-87514172-G-A is Benign according to our data. Variant chr6-87514172-G-A is described in ClinVar as Benign. ClinVar VariationId is 1260098.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020320.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARS2	NM_020320.5	MANE Select	c.*241C>T		3_prime_UTR	Exon 20 of 20	NP_064716.2	Q5T160
	RARS2	NM_001350505.2		c.*92C>T		3_prime_UTR	Exon 21 of 21	NP_001337434.1	A0A8I5KWC6
	RARS2	NM_001350506.2		c.*92C>T		3_prime_UTR	Exon 21 of 21	NP_001337435.1	A0A8I5KPZ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARS2	ENST00000369536.10	TSL:1 MANE Select	c.*241C>T		3_prime_UTR	Exon 20 of 20	ENSP00000358549.5	Q5T160
	RARS2	ENST00000691725.1		c.*92C>T		3_prime_UTR	Exon 21 of 21	ENSP00000509453.1	A0A8I5KWC6
	RARS2	ENST00000693431.1		c.*92C>T		3_prime_UTR	Exon 21 of 21	ENSP00000509147.1	A0A8I5KPZ0

Frequencies

GnomAD3 genomes AF: 0.0904 AC: 13735 AN: 151932 Hom.: 658 Cov.: 31

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.0714

Gnomad ASJ AF: 0.0507

Gnomad EAS AF: 0.0955

Gnomad SAS AF: 0.0908

Gnomad FIN AF: 0.0945

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0775

Gnomad OTH AF: 0.0848

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0905 AC: 13760 AN: 152050 Hom.: 664 Cov.: 31 AF XY: 0.0913 AC XY: 6787 AN XY: 74328

African (AFR) AF: 0.122 AC: 5063 AN: 41470

American (AMR) AF: 0.0714 AC: 1091 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0507 AC: 176 AN: 3472

East Asian (EAS) AF: 0.0957 AC: 496 AN: 5184

South Asian (SAS) AF: 0.0899 AC: 433 AN: 4818

European-Finnish (FIN) AF: 0.0945 AC: 997 AN: 10550

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0775 AC: 5268 AN: 67968

Other (OTH) AF: 0.0910 AC: 192 AN: 2110

Alfa AF: 0.0797 Hom.: 61

Bravo AF: 0.0891

Asia WGS AF: 0.135 AC: 469 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	3.0
DANN	Benign	0.56
PhyloP100		0.25

Splicing

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

Other links and lift over

dbSNP: rs35706399; hg19: chr6-88223890;