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GeneBe

11-75404831-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_001005.5(RPS3):c.698C>T(p.Pro233Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,612,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

RPS3
NM_001005.5 missense

Scores

2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.13
Variant links:
Genes affected
RPS3 (HGNC:10420): (ribosomal protein S3) 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, where it forms part of the domain where translation is initiated. The protein belongs to the S3P family of ribosomal proteins. Studies of the mouse and rat proteins have demonstrated that the protein has an extraribosomal role as an endonuclease involved in the repair of UV-induced DNA damage. The protein appears to be located in both the cytoplasm and nucleus but not in the nucleolus. Higher levels of expression of this gene in colon adenocarcinomas and adenomatous polyps compared to adjacent normal colonic mucosa have been observed. This gene is co-transcribed with the small nucleolar RNA genes U15A and U15B, which are located in its first and fifth introns, respectively. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP2
Missense variant where missense usually causes diseases, RPS3
BP4
Computational evidence support a benign effect (MetaRNN=0.03508836).
BS2
High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RPS3NM_001005.5 linkuse as main transcriptc.698C>T p.Pro233Leu missense_variant 6/7 ENST00000531188.6
RPS3NM_001260506.2 linkuse as main transcriptc.746C>T p.Pro249Leu missense_variant 6/7
RPS3NM_001256802.2 linkuse as main transcriptc.698C>T p.Pro233Leu missense_variant 6/7
RPS3NM_001260507.2 linkuse as main transcriptc.320C>T p.Pro107Leu missense_variant 5/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RPS3ENST00000531188.6 linkuse as main transcriptc.698C>T p.Pro233Leu missense_variant 6/71 NM_001005.5 P1P23396-1

Frequencies

GnomAD3 genomes
AF:
0.0000789
AC:
12
AN:
152174
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000565
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000101
AC:
25
AN:
247388
Hom.:
0
AF XY:
0.000127
AC XY:
17
AN XY:
134358
show subpopulations
Gnomad AFR exome
AF:
0.0000653
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000651
Gnomad NFE exome
AF:
0.0000538
Gnomad OTH exome
AF:
0.000333
GnomAD4 exome
AF:
0.0000479
AC:
70
AN:
1460542
Hom.:
0
Cov.:
31
AF XY:
0.0000482
AC XY:
35
AN XY:
726464
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.000525
Gnomad4 NFE exome
AF:
0.0000315
Gnomad4 OTH exome
AF:
0.0000663
GnomAD4 genome
AF:
0.0000788
AC:
12
AN:
152292
Hom.:
0
Cov.:
32
AF XY:
0.000107
AC XY:
8
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000565
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000428
Hom.:
0
Bravo
AF:
0.0000604
ExAC
AF:
0.000115
AC:
14

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 GeneticsJun 28, 2023The c.698C>T (p.P233L) alteration is located in exon 6 (coding exon 6) of the RPS3 gene. This alteration results from a C to T substitution at nucleotide position 698, causing the proline (P) at amino acid position 233 to be replaced by a leucine (L). 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
0.053
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.32
Cadd
Uncertain
25
Dann
Benign
0.69
DEOGEN2
Benign
0.093
T;.;T;T;T;T
Eigen
Benign
-0.47
Eigen_PC
Benign
-0.44
FATHMM_MKL
Uncertain
0.76
D
M_CAP
Benign
0.0055
T
MetaRNN
Benign
0.035
T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.20
N;.;.;N;.;N
MutationTaster
Benign
0.97
D;D;D;D;D;D;N
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
0.15
N;N;N;N;N;N
REVEL
Benign
0.076
Sift
Benign
0.052
T;D;D;T;D;T
Sift4G
Benign
0.21
T;T;T;T;T;T
Polyphen
0.0010
B;.;.;B;.;B
Vest4
0.28
MVP
0.22
MPC
1.3
ClinPred
0.030
T
GERP RS
0.81
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.082
gMVP
0.23

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs73006114; hg19: chr11-75115875; API