Variant 11-6601221-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000254605.11(RRP8):c.845G>A(p.Arg282His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000326 in 1,612,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R282C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

RRP8
ENST00000254605.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.78

Variant links:

Genes affected

RRP8 (HGNC:29030): (ribosomal RNA processing 8) Enables methylated histone binding activity. Involved in several processes, including cellular response to glucose starvation; intrinsic apoptotic signaling pathway by p53 class mediator; and regulation of gene expression. Located in several cellular components, including cytosol; nuclear lumen; and rDNA heterochromatin. Part of chromatin silencing complex. [provided by Alliance of Genome Resources, Apr 2022]

RRP8 links:

RRP8 (HGNC:):

RRP8 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34756076).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RRP8	NM_015324.4 linkuse as main transcript	c.845G>A	p.Arg282His	missense_variant	3/7	ENST00000254605.11	NP_056139.1	O43159

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RRP8	ENST00000254605.11 linkuse as main transcript	c.845G>A	p.Arg282His	missense_variant	3/7	1	NM_015324.4	ENSP00000254605.6		O43159

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000233

AC:

AN:

244422

Hom.:

AF XY:

0.000189

AC XY:

AN XY:

132388

show subpopulations

Gnomad AFR exome

AF:

0.0000635

Gnomad AMR exome

AF:

0.000501

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000993

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000328

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000329

AC:

480

AN:

1459866

Hom.:

Cov.:

AF XY:

0.000300

AC XY:

218

AN XY:

726090

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.000474

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0000465

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000396

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000302

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000427

Hom.:

Bravo

AF:

0.000370

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000815

AC:

ExAC

AF:

0.000173

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 14, 2024

The c.845G>A (p.R282H) alteration is located in exon 3 (coding exon 3) of the RRP8 gene. This alteration results from a G to A substitution at nucleotide position 845, causing the arginine (R) at amino acid position 282 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.0060

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Benign

0.72

LIST_S2

Pathogenic

0.97

M_CAP

Benign

0.0075

MetaRNN

Benign

0.35

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.7

REVEL

Benign

0.11

Sift

Uncertain

0.014

Sift4G

Uncertain

0.027

Polyphen

0.99

Vest4

0.43

MVP

0.78

MPC

0.046

ClinPred

0.17

GERP RS

5.9

Varity_R

0.21

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over