6-34418416-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BS2

The NM_001014.5(RPS10):c.409G>A(p.Asp137Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,880 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: 0.0000034 ( 0 hom. )

Consequence

RPS10
NM_001014.5 missense

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:49181): (RPS10-NUDT3 readthrough) This locus represents naturally occurring read-through transcription between the neighboring RPS10 (ribosomal protein S10) and NUDT3 (nudix (nucleoside diphosphate linked moiety X)-type motif 3) genes on chromosome 6. The read-through transcript produces a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Feb 2011]

RPS10-NUDT3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS10	NM_001014.5 link	c.409G>A	p.Asp137Asn	missense_variant	Exon 5 of 6	ENST00000648437.1	NP_001005.1	P46783
RPS10-NUDT3	NM_001202470.3 link	c.409G>A	p.Asp137Asn	missense_variant	Exon 5 of 9		NP_001189399.1	A0A1W2PQS6
RPS10	NM_001203245.3 link	c.409G>A	p.Asp137Asn	missense_variant	Exon 5 of 6		NP_001190174.1	P46783
RPS10	NM_001204091.2 link	c.409G>A	p.Asp137Asn	missense_variant	Exon 5 of 6		NP_001191020.1	P46783

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS10	ENST00000648437.1 link	c.409G>A	p.Asp137Asn	missense_variant	Exon 5 of 6		NM_001014.5	ENSP00000497917.1		P46783
RPS10-NUDT3	ENST00000639725.1 link	c.409G>A	p.Asp137Asn	missense_variant	Exon 5 of 9	5		ENSP00000492441.1		A0A1W2PQS6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251462

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000480

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.409G>A (p.D137N) alteration is located in exon 5 (coding exon 4) of the RPS10-NUDT3 gene. This alteration results from a G to A substitution at nucleotide position 409, causing the aspartic acid (D) at amino acid position 137 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Diamond-Blackfan anemia

Uncertain:1

Dec 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 137 of the RPS10 protein (p.Asp137Asn). This variant is present in population databases (rs768038583, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RPS10-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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

Pathogenic

0.92

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

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

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.37

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

M_CAP

Benign

0.073

MetaRNN

Uncertain

0.51

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

MetaSVM

Benign

-0.29

MutationAssessor

Uncertain

2.6

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

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.6

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

REVEL

Uncertain

0.41

Sift

Benign

0.048

.;.;.;.;.;D;.;.;T;.

Sift4G

Benign

0.071

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

Polyphen

0.071

.;.;B;B;B;.;.;B;B;.

Vest4

0.57, 0.56

MutPred

0.32

Loss of ubiquitination at K138 (P = 0.0272);Loss of ubiquitination at K138 (P = 0.0272);Loss of ubiquitination at K138 (P = 0.0272);Loss of ubiquitination at K138 (P = 0.0272);Loss of ubiquitination at K138 (P = 0.0272);Loss of ubiquitination at K138 (P = 0.0272);Loss of ubiquitination at K138 (P = 0.0272);Loss of ubiquitination at K138 (P = 0.0272);Loss of ubiquitination at K138 (P = 0.0272);Loss of ubiquitination at K138 (P = 0.0272);

MVP

0.57

MPC

1.0

ClinPred

0.96

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.64

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over