4-151104535-C-A

Position:

• chr4-151104535-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001006.5(RPS3A):​c.737C>A​(p.Thr246Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000264 in 1,555,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000094 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: RPS3A NM_001006.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.76

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12789026).
• BS2: High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS3A	NM_001006.5	c.737C>A	p.Thr246Lys	missense_variant	6/6	ENST00000274065.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS3A	ENST00000274065.9	c.737C>A	p.Thr246Lys	missense_variant	6/6	1	NM_001006.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000940 AC: 13 AN: 138364 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000197

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000809 AC: 17 AN: 210240 Hom.: 0 AF XY: 0.0000941 AC XY: 11 AN XY: 116844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000184

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000127

Gnomad OTH exome AF: 0.000191

GnomAD4 exome AF: 0.000281 AC: 398 AN: 1416924 Hom.: 0 Cov.: 33 AF XY: 0.000271 AC XY: 191 AN XY: 704994

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000517

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000343

Gnomad4 OTH exome AF: 0.000323

GnomAD4 genome AF: 0.0000940 AC: 13 AN: 138364 Hom.: 0 Cov.: 30 AF XY: 0.0000455 AC XY: 3 AN XY: 65892

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000197

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000779 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.737C>A (p.T246K) alteration is located in exon 6 (coding exon 6) of the RPS3A gene. This alteration results from a C to A substitution at nucleotide position 737, causing the threonine (T) at amino acid position 246 to be replaced by a lysine (K). 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	Uncertain	0.51
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T;T;T;T;T
Eigen	Benign	0.034
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;.;D;D
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.1	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.3	N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.50	T;T;T;T;T
Sift4G	Benign	0.44	T;T;T;T;T
Polyphen		0.0030	B;.;.;.;.
Vest4		0.36
MutPred		0.27		Gain of ubiquitination at T246 (P = 0.0037);.;.;.;.;
MVP		0.51
MPC		1.2
ClinPred		0.19	T
GERP RS		5.7
Varity_R		0.16
gMVP		0.59

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

LitVar

Other links and lift over

dbSNP: rs752826990; hg19: chr4-152025687;