chr11-75404831-C-A

Variant names:

• chr11-75404831-C-A
• rs73006114
• NM_001005.5:c.698C>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001005.5(RPS3):​c.698C>A​(p.Pro233Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,612,816 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0019 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (5 hom.)
• Consequence: RPS3 NM_001005.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.13

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049730837).
• BS2: High AC in GnomAd4 at 286 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS3	NM_001005.5	c.698C>A	p.Pro233Gln	missense_variant	Exon 6 of 7	ENST00000531188.6	NP_000996.2
RPS3	NM_001260506.2	c.746C>A	p.Pro249Gln	missense_variant	Exon 6 of 7		NP_001247435.1
RPS3	NM_001256802.2	c.698C>A	p.Pro233Gln	missense_variant	Exon 6 of 7		NP_001243731.1
RPS3	NM_001260507.2	c.320C>A	p.Pro107Gln	missense_variant	Exon 5 of 6		NP_001247436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS3	ENST00000531188.6	c.698C>A	p.Pro233Gln	missense_variant	Exon 6 of 7	1	NM_001005.5	ENSP00000434643.1

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 287 AN: 152174 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00250

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00142 AC: 351 AN: 247388 Hom.: 0 AF XY: 0.00153 AC XY: 205 AN XY: 134358

Gnomad AFR exome AF: 0.000522

Gnomad AMR exome AF: 0.00183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00239

Gnomad OTH exome AF: 0.00183

GnomAD4 exome AF: 0.00195 AC: 2851 AN: 1460524 Hom.: 5 Cov.: 31 AF XY: 0.00193 AC XY: 1402 AN XY: 726454

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00237

Gnomad4 OTH exome AF: 0.00164

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152292 Hom.: 3 Cov.: 32 AF XY: 0.00193 AC XY: 144 AN XY: 74474

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00250

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000899 Hom.: 0

Bravo AF: 0.00241

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00268 AC: 23

ExAC AF: 0.00144 AC: 175

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Benign	0.81
DEOGEN2	Benign	0.084	T;.;T;T;T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.81	.;T;T;.;T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.0050	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;.;.;L;.;L
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.11	N;N;N;N;N;N
REVEL	Benign	0.078
Sift	Benign	0.12	T;T;D;T;T;T
Sift4G	Benign	0.23	T;T;T;T;T;T
Polyphen		0.28	B;.;.;B;.;B
Vest4		0.25
MVP		0.26
MPC		1.2
ClinPred		0.0030	T
GERP RS		0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs73006114; hg19: chr11-75115875; COSMIC: COSV99584493; COSMIC: COSV99584493;