6-34418416-C-T

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

3
7
9

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-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]

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
RPS10NM_001014.5 linkc.409G>A p.Asp137Asn missense_variant Exon 5 of 6 ENST00000648437.1 NP_001005.1 P46783
RPS10-NUDT3NM_001202470.3 linkc.409G>A p.Asp137Asn missense_variant Exon 5 of 9 NP_001189399.1 A0A1W2PQS6
RPS10NM_001203245.3 linkc.409G>A p.Asp137Asn missense_variant Exon 5 of 6 NP_001190174.1 P46783
RPS10NM_001204091.2 linkc.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
RPS10ENST00000648437.1 linkc.409G>A p.Asp137Asn missense_variant Exon 5 of 6 NM_001014.5 ENSP00000497917.1 P46783
RPS10-NUDT3ENST00000639725.1 linkc.409G>A p.Asp137Asn missense_variant Exon 5 of 9 5 ENSP00000492441.1 A0A1W2PQS6

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251462
Hom.:
0
AF XY:
0.00000736
AC XY:
1
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:
5
AN:
1461880
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
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.:
32
Alfa
AF:
0.0000480
Hom.:
0
ExAC
AF:
0.00000824
AC:
1

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
T
BayesDel_noAF
Benign
-0.26
CADD
Uncertain
24
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
D
LIST_S2
Benign
0.37
.;T;.;.;.;T;T;.;T;T
M_CAP
Benign
0.073
D
MetaRNN
Uncertain
0.51
D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.29
T
MutationAssessor
Uncertain
2.6
.;.;M;M;M;.;.;M;M;.
PrimateAI
Pathogenic
0.82
D
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
D
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.

Other links and lift over

dbSNP: rs768038583; hg19: chr6-34386193; COSMIC: COSV58241886; COSMIC: COSV58241886; API