NM_020320.5:c.*101dupT

Variant names:

• chr6-87514311-C-CA
• rs5878032
• NM_020320.5:c.*101dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_020320.5(RARS2):​c.*101dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 566,554 control chromosomes in the GnomAD database, including 464 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.095 (442 hom., cov: 0)
  • Exomes 𝑓: 0.13 (22 hom.)
• Consequence: RARS2 NM_020320.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.613
• Publications: 1 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 -10 ACMG points.

• BP6: Variant 6-87514311-C-CA is Benign according to our data. Variant chr6-87514311-C-CA is described in ClinVar as Benign. ClinVar VariationId is 1221069.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.104 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.*101dupT		3_prime_UTR	Exon 20 of 20	NP_064716.2	Q5T160
	RARS2	NM_001318785.2		c.*101dupT		3_prime_UTR	Exon 19 of 19	NP_001305714.1	H0UI22
	RARS2	NM_001350507.2		c.*101dupT		3_prime_UTR	Exon 21 of 21	NP_001337436.1	H0UI22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARS2	ENST00000369536.10	TSL:1 MANE Select	c.*101dupT		3_prime_UTR	Exon 20 of 20	ENSP00000358549.5	Q5T160
	RARS2	ENST00000685408.1		c.*101dupT		3_prime_UTR	Exon 21 of 21	ENSP00000509026.1	H0UI22
	RARS2	ENST00000689174.1		c.*101dupT		3_prime_UTR	Exon 20 of 20	ENSP00000510542.1	H0UI22

Frequencies

GnomAD3 genomes AF: 0.0952 AC: 10671 AN: 112042 Hom.: 439 Cov.: 0

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.0531

Gnomad AMR AF: 0.0724

Gnomad ASJ AF: 0.0620

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.0593

Gnomad NFE AF: 0.0937

Gnomad OTH AF: 0.0966

GnomAD4 exome AF: 0.130 AC: 58892 AN: 454480 Hom.: 22 AF XY: 0.129 AC XY: 31590 AN XY: 244210

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.147 AC: 1510 AN: 10306

American (AMR) AF: 0.0894 AC: 1619 AN: 18112

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 1438 AN: 12646

East Asian (EAS) AF: 0.147 AC: 2870 AN: 19478

South Asian (SAS) AF: 0.120 AC: 5831 AN: 48670

European-Finnish (FIN) AF: 0.136 AC: 3773 AN: 27652

Middle Eastern (MID) AF: 0.128 AC: 195 AN: 1522

European-Non Finnish (NFE) AF: 0.132 AC: 38846 AN: 295092

Other (OTH) AF: 0.134 AC: 2810 AN: 21002

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0953 AC: 10679 AN: 112074 Hom.: 442 Cov.: 0 AF XY: 0.0953 AC XY: 5088 AN XY: 53382

African (AFR) AF: 0.107 AC: 3069 AN: 28752

American (AMR) AF: 0.0723 AC: 832 AN: 11502

Ashkenazi Jewish (ASJ) AF: 0.0620 AC: 172 AN: 2776

East Asian (EAS) AF: 0.111 AC: 441 AN: 3960

South Asian (SAS) AF: 0.105 AC: 375 AN: 3584

European-Finnish (FIN) AF: 0.102 AC: 607 AN: 5950

Middle Eastern (MID) AF: 0.0541 AC: 12 AN: 222

European-Non Finnish (NFE) AF: 0.0937 AC: 4984 AN: 53210

Other (OTH) AF: 0.104 AC: 153 AN: 1478

Alfa AF: 0.0383 Hom.: 171

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	RARS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.61

Splicing

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

Other links and lift over

dbSNP: rs5878032; hg19: chr6-88224029;