Genetic Variant RPS8:p.Arg49Gly (chr1-44776708-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001012.2(RPS8):c.145C>G(p.Arg49Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R49W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

RPS8
NM_001012.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.75

Publications

0 publications found

Variant links:

Genes affected

RPS8 (HGNC:10441): (ribosomal protein S8) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 40S subunit. The protein belongs to the S8E family of ribosomal proteins. It is located in the cytoplasm. Increased expression of this gene in colorectal tumors and colon polyps compared to matched normal colonic mucosa has been observed. This gene is co-transcribed with the small nucleolar RNA genes U38A, U38B, U39, and U40, which are located in its fourth, fifth, first, and second introns, respectively. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

RPS8 links:

SNORD46 (HGNC:10186): (small nucleolar RNA, C/D box 46)

SNORD46 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.867

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001012.2. 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
	RPS8	NM_001012.2	MANE Select	c.145C>G	p.Arg49Gly	missense	Exon 3 of 6	NP_001003.1	P62241
	SNORD46	NR_000024.2		n.*119C>G		downstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPS8	ENST00000396651.8	TSL:1 MANE Select	c.145C>G	p.Arg49Gly	missense	Exon 3 of 6	ENSP00000379888.3	P62241
RPS8	ENST00000485390.5	TSL:1	n.539C>G		non_coding_transcript_exon	Exon 2 of 5
RPS8	ENST00000932906.1		c.145C>G	p.Arg49Gly	missense	Exon 3 of 6	ENSP00000602965.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.073

MetaRNN

Pathogenic

0.87

MetaSVM

Uncertain

-0.10

MutationAssessor

Pathogenic

3.9

PhyloP100

3.7

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-6.2

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.012

Polyphen

1.0

Vest4

0.85

MutPred

0.72

Loss of methylation at R49 (P = 0.0141)

MVP

0.72

MPC

2.6

ClinPred

0.99

GERP RS

3.9

Varity_R

0.99

gMVP

0.99

Mutation Taster

=14/86

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over