Genetic Variant RARS2:c.*97_*101delTTTTT (chr6-87514311-CAAAAA-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001350505.2(RARS2):c.1723-8_1723-4delTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 574,736 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 0.0000089 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

RARS2
NM_001350505.2 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.613

Publications

1 publications found

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 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

RARS2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RARS2	NM_020320.5	MANE Select	c.97_101delTTTTT	3_prime_UTR	Exon 20 of 20	NP_064716.2	Q5T160
RARS2	NM_001318785.2		c.97_101delTTTTT	3_prime_UTR	Exon 19 of 19	NP_001305714.1	H0UI22
RARS2	NM_001350507.2		c.97_101delTTTTT	3_prime_UTR	Exon 21 of 21	NP_001337436.1	H0UI22

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RARS2	ENST00000369536.10	TSL:1 MANE Select	c.97_101delTTTTT	3_prime_UTR	Exon 20 of 20	ENSP00000358549.5	Q5T160
RARS2	ENST00000685408.1		c.97_101delTTTTT	3_prime_UTR	Exon 21 of 21	ENSP00000509026.1	H0UI22
RARS2	ENST00000689174.1		c.97_101delTTTTT	3_prime_UTR	Exon 20 of 20	ENSP00000510542.1	H0UI22

Frequencies

GnomAD3 genomes

AF:

0.00000891

AC:

AN:

112202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000541

AC:

AN:

462534

Hom.:

AF XY:

0.0000523

AC XY:

AN XY:

248778

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

10552

American (AMR)

AF:

0.0000540

AC:

AN:

18506

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12842

East Asian (EAS)

AF:

0.00

AC:

AN:

19896

South Asian (SAS)

AF:

0.0000400

AC:

AN:

49978

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28072

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1548

European-Non Finnish (NFE)

AF:

0.0000734

AC:

AN:

299772

Other (OTH)

AF:

0.00

AC:

AN:

21368

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000842606), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000891

AC:

AN:

112202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

53390

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28738

American (AMR)

AF:

0.00

AC:

AN:

11498

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2778

East Asian (EAS)

AF:

0.00

AC:

AN:

3982

South Asian (SAS)

AF:

0.00

AC:

AN:

3618

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5964

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53276

Other (OTH)

AF:

0.00

AC:

AN:

1470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Publications

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6-87514311-CAAAAAAAAA-CAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over