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GeneBe

8-144791997-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001317782.2(RPL8):c.133G>A(p.Val45Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000343 in 1,456,296 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

RPL8
NM_001317782.2 missense

Scores

2
3
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.61
Variant links:
Genes affected
RPL8 (HGNC:10368): (ribosomal protein L8) 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 60S subunit. The protein belongs to the L2P family of ribosomal proteins. It is located in the cytoplasm. In rat, the protein associates with the 5.8S rRNA, very likely participates in the binding of aminoacyl-tRNA, and is a constituent of the elongation factor 2-binding site at the ribosomal subunit interface. Alternatively spliced transcript variants encoding the same protein exist. 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]
MIR6850 (HGNC:50093): (microRNA 6850) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RPL8NM_001317782.2 linkuse as main transcriptc.133G>A p.Val45Ile missense_variant 1/5 ENST00000528957.6
MIR6850NR_106909.1 linkuse as main transcript upstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RPL8ENST00000528957.6 linkuse as main transcriptc.133G>A p.Val45Ile missense_variant 1/51 NM_001317782.2 P1
MIR6850ENST00000612162.1 linkuse as main transcript upstream_gene_variant

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000343
AC:
5
AN:
1456296
Hom.:
0
Cov.:
33
AF XY:
0.00000414
AC XY:
3
AN XY:
723918
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000451
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

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 submitterclinical testingAmbry GeneticsSep 27, 2021The c.133G>A (p.V45I) alteration is located in exon 2 (coding exon 1) of the RPL8 gene. This alteration results from a G to A substitution at nucleotide position 133, causing the valine (V) at amino acid position 45 to be replaced by an isoleucine (I). 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
0.12
BayesDel_addAF
Benign
-0.019
T
BayesDel_noAF
Benign
-0.27
Cadd
Uncertain
24
Dann
Uncertain
0.99
DEOGEN2
Benign
0.082
T;T;T;T;.;T
Eigen
Benign
0.13
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Pathogenic
0.99
D
M_CAP
Benign
0.0088
T
MetaRNN
Uncertain
0.60
D;D;D;D;D;D
MetaSVM
Benign
-0.63
T
MutationAssessor
Benign
1.6
L;.;L;L;.;.
MutationTaster
Benign
1.0
D;D;D;N
PrimateAI
Pathogenic
0.88
D
PROVEAN
Benign
-0.85
N;N;N;N;N;N
REVEL
Benign
0.21
Sift
Benign
0.12
T;T;T;T;T;T
Sift4G
Benign
0.28
T;T;T;T;.;T
Polyphen
0.0050
B;.;B;B;.;.
Vest4
0.74
MutPred
0.74
Gain of ubiquitination at K46 (P = 0.0898);Gain of ubiquitination at K46 (P = 0.0898);Gain of ubiquitination at K46 (P = 0.0898);Gain of ubiquitination at K46 (P = 0.0898);Gain of ubiquitination at K46 (P = 0.0898);Gain of ubiquitination at K46 (P = 0.0898);
MVP
0.37
MPC
0.84
ClinPred
0.96
D
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.13
gMVP
0.62

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-146017382; API