4-151104553-G-A

Variant names:

• chr4-151104553-G-A
• NM_001006.5:c.755G>A

Variant summary

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

The NM_001006.5(RPS3A):​c.755G>A​(p.Arg252Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,407,252 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RPS3A NM_001006.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.97

Genes affected

RPS3A (HGNC:10421): (ribosomal protein S3A) 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. The protein belongs to the S3AE family of ribosomal proteins. It is located in the cytoplasm. Disruption of the gene encoding rat ribosomal protein S3a, also named v-fos transformation effector protein, in v-fos-transformed rat cells results in reversion of the transformed phenotype. This gene is co-transcribed with the U73A and U73B small nucleolar RNA genes, which are located in its fourth and third introns, respectively. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, May 2012]

SH3D19 (HGNC:30418): (SH3 domain containing 19) This gene encodes a multiple SH3 domain-containing protein, which interacts with other proteins, such as EBP and members of ADAM family, via the SH3 domains. This protein may be involved in suppression of Ras-induced cellular transformation and Ras-mediated activation of ELK1 by EBP, and regulation of ADAM proteins in the signaling of EGFR-ligand shedding. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

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 rank	MANE	Protein	UniProt
RPS3A	NM_001006.5	c.755G>A	p.Arg252Gln	missense_variant	Exon 6 of 6	ENST00000274065.9	NP_000997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS3A	ENST00000274065.9	c.755G>A	p.Arg252Gln	missense_variant	Exon 6 of 6	1	NM_001006.5	ENSP00000346050.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1407252 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 700158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000261

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 Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 15, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.755G>A (p.R252Q) alteration is located in exon 6 (coding exon 6) of the RPS3A gene. This alteration results from a G to A substitution at nucleotide position 755, causing the arginine (R) at amino acid position 252 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	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	T;T;T;T;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;.;D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.52	D;D;D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.1	M;.;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.2	N;D;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.058	T;D;D;D;D
Sift4G	Benign	0.20	T;T;T;T;T
Polyphen		0.82	P;.;.;.;.
Vest4		0.31
MutPred		0.33		Gain of methylation at K249 (P = 0.0934);.;.;.;.;
MVP		0.77
MPC		1.2
ClinPred		0.86	D
GERP RS		4.8
Varity_R		0.20
gMVP		0.54

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: chr4-152025705; COSMIC: COSV99923665; COSMIC: COSV99923665;