6-34418422-C-A

Position:

chr6-34418422-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001014.5(RPS10):c.403G>T(p.Gly135Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

RPS10
NM_001014.5 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.64

Variant links:

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 links:

RPS10-NUDT3 (HGNC:):

RPS10-NUDT3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.857

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RPS10	NM_001014.5 linkuse as main transcript	c.403G>T	p.Gly135Cys	missense_variant, splice_region_variant	5/6	ENST00000648437.1	NP_001005.1
RPS10-NUDT3	NM_001202470.3 linkuse as main transcript	c.403G>T	p.Gly135Cys	missense_variant, splice_region_variant	5/9		NP_001189399.1
RPS10	NM_001203245.3 linkuse as main transcript	c.403G>T	p.Gly135Cys	missense_variant, splice_region_variant	5/6		NP_001190174.1
RPS10	NM_001204091.2 linkuse as main transcript	c.403G>T	p.Gly135Cys	missense_variant, splice_region_variant	5/6		NP_001191020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS10	ENST00000648437.1 linkuse as main transcript	c.403G>T	p.Gly135Cys	missense_variant, splice_region_variant	5/6		NM_001014.5	ENSP00000497917	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2022

The c.403G>T (p.G135C) alteration is located in exon 5 (coding exon 4) of the RPS10-NUDT3 gene. This alteration results from a G to T substitution at nucleotide position 403, causing the glycine (G) at amino acid position 135 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Diamond-Blackfan anemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 135 of the RPS10 protein (p.Gly135Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RPS10-related conditions. ClinVar contains an entry for this variant (Variation ID: 2302403). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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

0.52

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

.;.;T;T;T;.;.;T;T;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;D;.;.;.;D;D;.;D;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.86

D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.41

MutationAssessor

Pathogenic

3.1

.;.;M;M;M;.;.;M;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-6.2

.;.;.;.;.;D;.;.;D;.

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0010

.;.;.;.;.;D;.;.;D;.

Sift4G

Uncertain

0.0030

.;.;.;.;D;D;.;.;D;.

Polyphen

1.0

.;.;D;D;D;.;.;D;D;.

Vest4

0.62, 0.63

MutPred

0.25

Gain of catalytic residue at P134 (P = 0.0244);Gain of catalytic residue at P134 (P = 0.0244);Gain of catalytic residue at P134 (P = 0.0244);Gain of catalytic residue at P134 (P = 0.0244);Gain of catalytic residue at P134 (P = 0.0244);Gain of catalytic residue at P134 (P = 0.0244);Gain of catalytic residue at P134 (P = 0.0244);Gain of catalytic residue at P134 (P = 0.0244);Gain of catalytic residue at P134 (P = 0.0244);Gain of catalytic residue at P134 (P = 0.0244);

MVP

0.79

MPC

2.2

ClinPred

0.99

GERP RS

4.9

Varity_R

0.80

gMVP

0.86

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over