11-75404831-C-T

Position:

chr11-75404831-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_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. 13/20 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

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]

RPS3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03508836).

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RPS3	NM_001005.5 linkuse as main transcript	c.698C>T	p.Pro233Leu	missense_variant	6/7	ENST00000531188.6
RPS3	NM_001260506.2 linkuse as main transcript	c.746C>T	p.Pro249Leu	missense_variant	6/7
RPS3	NM_001256802.2 linkuse as main transcript	c.698C>T	p.Pro233Leu	missense_variant	6/7
RPS3	NM_001260507.2 linkuse as main transcript	c.320C>T	p.Pro107Leu	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS3	ENST00000531188.6 linkuse as main transcript	c.698C>T	p.Pro233Leu	missense_variant	6/7	1	NM_001005.5	P1	P23396-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152174

Hom.:

Cov.:

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:

AN:

247388

Hom.:

AF XY:

0.000127

AC XY:

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:

AN:

1460542

Hom.:

Cov.:

AF XY:

0.0000482

AC XY:

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:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

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.:

Bravo

AF:

0.0000604

ExAC

AF:

0.000115

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

Jun 28, 2023

The 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

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

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

LIST_S2

Benign

0.76

.;T;T;.;T;T

M_CAP

Benign

0.0055

MetaRNN

Benign

0.035

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.20

N;.;.;N;.;N

MutationTaster

Benign

0.97

D;D;D;D;D;D;N

PrimateAI

Uncertain

0.52

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

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.

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