rs1004018136

Variant names:

• chr16-18789026-A-G
• rs1004018136
• NM_001019.5:c.88T>C

Variant summary

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

The NM_001019.5(RPS15A):​c.88T>C​(p.Cys30Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RPS15A NM_001019.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.11

Genes affected

RPS15A (HGNC:10389): (ribosomal protein S15a) 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 S8P family of ribosomal proteins. It is located in the cytoplasm. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

ENSG00000260342 (HGNC:):

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
RPS15A	NM_001019.5	c.88T>C	p.Cys30Arg	missense_variant	Exon 2 of 5	ENST00000322989.8	NP_001010.2
RPS15A	NM_001030009.2	c.88T>C	p.Cys30Arg	missense_variant	Exon 2 of 5		NP_001025180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS15A	ENST00000322989.8	c.88T>C	p.Cys30Arg	missense_variant	Exon 2 of 5	1	NM_001019.5	ENSP00000318646.4
ENSG00000260342	ENST00000567078.2	c.586T>C	p.Cys196Arg	missense_variant	Exon 6 of 7	3		ENSP00000454746.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.88T>C (p.C30R) alteration is located in exon 2 (coding exon 1) of the RPS15A gene. This alteration results from a T to C substitution at nucleotide position 88, causing the cysteine (C) at amino acid position 30 to be replaced by an arginine (R). 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	0.98
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T;T;.;T;T;.
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	.;.;.;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.66	D;D;D;D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Pathogenic	3.2	M;M;.;M;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.2	D;D;.;D;.;D
REVEL	Benign	0.28
Sift	Uncertain	0.017	D;D;.;D;.;D
Sift4G	Uncertain	0.026	D;D;D;D;D;D
Polyphen		0.0030	B;B;.;B;.;.
Vest4		0.89
MutPred		0.63		Gain of solvent accessibility (P = 0.0328);Gain of solvent accessibility (P = 0.0328);Gain of solvent accessibility (P = 0.0328);Gain of solvent accessibility (P = 0.0328);Gain of solvent accessibility (P = 0.0328);.;
MVP		0.43
MPC		2.4
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.91
gMVP		0.95

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: rs1004018136; hg19: chr16-18800348;