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GeneBe

8-144791994-T-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001317782.2(RPL8):c.136A>C(p.Lys46Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000118 in 1,608,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

RPL8
NM_001317782.2 missense, splice_region

Scores

3
5
10
Splicing: ADA: 0.8607
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.70
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 Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.38730606).
BS2
High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RPL8NM_001317782.2 linkuse as main transcriptc.136A>C p.Lys46Gln missense_variant, splice_region_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.136A>C p.Lys46Gln missense_variant, splice_region_variant 1/51 NM_001317782.2 P1
MIR6850ENST00000612162.1 linkuse as main transcript upstream_gene_variant

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152138
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000288
AC:
7
AN:
243350
Hom.:
0
AF XY:
0.0000226
AC XY:
3
AN XY:
132488
show subpopulations
Gnomad AFR exome
AF:
0.000388
Gnomad AMR exome
AF:
0.0000293
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000755
AC:
11
AN:
1456642
Hom.:
0
Cov.:
33
AF XY:
0.00000829
AC XY:
6
AN XY:
724144
show subpopulations
Gnomad4 AFR exome
AF:
0.000270
Gnomad4 AMR exome
AF:
0.0000226
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000525
AC:
8
AN:
152256
Hom.:
0
Cov.:
33
AF XY:
0.0000537
AC XY:
4
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.000168
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000604
ExAC
AF:
0.0000247
AC:
3

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 GeneticsDec 20, 2021The c.136A>C (p.K46Q) alteration is located in exon 2 (coding exon 1) of the RPL8 gene. This alteration results from a A to C substitution at nucleotide position 136, causing the lysine (K) at amino acid position 46 to be replaced by a glutamine (Q). 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
0.31
BayesDel_addAF
Benign
-0.095
T
BayesDel_noAF
Uncertain
-0.070
Cadd
Pathogenic
29
Dann
Uncertain
0.99
DEOGEN2
Benign
0.19
T;T;T;T;.;T
Eigen
Uncertain
0.38
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Pathogenic
0.99
D
M_CAP
Benign
0.0093
T
MetaRNN
Benign
0.39
T;T;T;T;T;T
MetaSVM
Benign
-0.77
T
MutationAssessor
Pathogenic
3.4
M;.;M;M;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Uncertain
-2.9
D;D;D;D;D;D
REVEL
Benign
0.22
Sift
Benign
0.033
D;D;D;D;D;D
Sift4G
Benign
0.32
T;D;T;T;.;T
Polyphen
0.84
P;.;P;P;.;.
Vest4
0.77
MVP
0.68
MPC
1.1
ClinPred
0.27
T
GERP RS
5.5
Varity_R
0.65
gMVP
0.63

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.86
dbscSNV1_RF
Benign
0.67
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

LitVar

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

Other links and lift over

dbSNP: rs527249558; hg19: chr8-146017379; API