6-34418400-G-A

Position:

• chr6-34418400-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001014.5(RPS10):​c.425C>T​(p.Ala142Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,158 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 0.0000066 (0 hom., cov: 32)
• Consequence: RPS10 NM_001014.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.65

Genes affected

RPS10 (HGNC:10383): (ribosomal protein S10) 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 S10E family of ribosomal proteins. It is located in the cytoplasm. Variable expression of this gene in colorectal cancers compared to adjacent normal tissues has been observed, although no correlation between the level of expression and the severity of the disease has been found. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. Alternate splicing results in multiple transcript variants that encode the same protein. Naturally occurring read-through transcription occurs between this locus and the neighboring locus NUDT3 (nudix (nucleoside diphosphate linked moiety X)-type motif 3).[provided by RefSeq, Feb 2011]

RPS10-NUDT3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26416168).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPS10	NM_001014.5	c.425C>T	p.Ala142Val	missense_variant	5/6	ENST00000648437.1	NP_001005.1
RPS10-NUDT3	NM_001202470.3	c.425C>T	p.Ala142Val	missense_variant	5/9		NP_001189399.1
RPS10	NM_001203245.3	c.425C>T	p.Ala142Val	missense_variant	5/6		NP_001190174.1
RPS10	NM_001204091.2	c.425C>T	p.Ala142Val	missense_variant	5/6		NP_001191020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS10	ENST00000648437.1	c.425C>T	p.Ala142Val	missense_variant	5/6		NM_001014.5	ENSP00000497917	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74330

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: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diamond-Blackfan anemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 29, 2021

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with RPS10-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 142 of the RPS10 protein (p.Ala142Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	.;.;T;T;T;.;.;T;T;.
Eigen	Benign	0.095
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.75	.;T;.;.;.;T;T;.;T;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.5	.;.;L;L;L;.;.;L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.35	.;.;.;.;.;N;.;.;N;.
REVEL	Uncertain	0.41
Sift	Benign	0.63	.;.;.;.;.;T;.;.;T;.
Sift4G	Benign	0.71	.;.;.;.;T;T;.;.;T;.
Polyphen		0.30	.;.;B;B;B;.;.;B;B;.
Vest4		0.52, 0.51
MutPred		0.12		Loss of relative solvent accessibility (P = 0.107);Loss of relative solvent accessibility (P = 0.107);Loss of relative solvent accessibility (P = 0.107);Loss of relative solvent accessibility (P = 0.107);Loss of relative solvent accessibility (P = 0.107);Loss of relative solvent accessibility (P = 0.107);Loss of relative solvent accessibility (P = 0.107);Loss of relative solvent accessibility (P = 0.107);Loss of relative solvent accessibility (P = 0.107);Loss of relative solvent accessibility (P = 0.107);
MVP		0.41
MPC		1.5
ClinPred		0.89	D
GERP RS		4.9
Varity_R		0.15
gMVP		0.69

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: rs1765648018; hg19: chr6-34386177;