6-87514311-CAAAAAAAAA-CAAAAAA

Variant names:

• chr6-87514311-CAAA-C
• rs5878032
• NM_020320.5:c.*99_*101delTTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_001350505.2(RARS2):​c.1723-6_1723-4delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 571,850 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0031 (0 hom.)
• Consequence: RARS2 NM_001350505.2 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0025 (280/112220) while in subpopulation AFR AF = 0.00934 (269/28806). AF 95% confidence interval is 0.00842. There are 0 homozygotes in GnomAd4. There are 134 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001350505.2. 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.*99_*101delTTT		3_prime_UTR	Exon 20 of 20	NP_064716.2	Q5T160
	RARS2	NM_001318785.2		c.*99_*101delTTT		3_prime_UTR	Exon 19 of 19	NP_001305714.1	H0UI22
	RARS2	NM_001350507.2		c.*99_*101delTTT		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.*99_*101delTTT		3_prime_UTR	Exon 20 of 20	ENSP00000358549.5	Q5T160
	RARS2	ENST00000685408.1		c.*99_*101delTTT		3_prime_UTR	Exon 21 of 21	ENSP00000509026.1	H0UI22
	RARS2	ENST00000689174.1		c.*99_*101delTTT		3_prime_UTR	Exon 20 of 20	ENSP00000510542.1	H0UI22

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 280 AN: 112190 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00936

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000609

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: 0.0000375

Gnomad OTH AF: 0.00136

GnomAD4 exome AF: 0.00309 AC: 1422 AN: 459630 Hom.: 0 AF XY: 0.00299 AC XY: 738 AN XY: 247212

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

African (AFR) AF: 0.00762 AC: 80 AN: 10494

American (AMR) AF: 0.00463 AC: 85 AN: 18342

Ashkenazi Jewish (ASJ) AF: 0.00376 AC: 48 AN: 12768

East Asian (EAS) AF: 0.00339 AC: 67 AN: 19786

South Asian (SAS) AF: 0.00242 AC: 120 AN: 49574

European-Finnish (FIN) AF: 0.00276 AC: 77 AN: 27912

Middle Eastern (MID) AF: 0.00390 AC: 6 AN: 1540

European-Non Finnish (NFE) AF: 0.00291 AC: 868 AN: 297980

Other (OTH) AF: 0.00334 AC: 71 AN: 21234

⚠️ 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: 0.00250 AC: 280 AN: 112220 Hom.: 0 Cov.: 0 AF XY: 0.00251 AC XY: 134 AN XY: 53438

African (AFR) AF: 0.00934 AC: 269 AN: 28806

American (AMR) AF: 0.000608 AC: 7 AN: 11516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2778

East Asian (EAS) AF: 0.00 AC: 0 AN: 3968

South Asian (SAS) AF: 0.00 AC: 0 AN: 3590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5956

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 222

European-Non Finnish (NFE) AF: 0.0000375 AC: 2 AN: 53268

Other (OTH) AF: 0.00136 AC: 2 AN: 1476

Alfa AF: 0.00 Hom.: 171

ClinVar

Not reported in ClinVar

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;