18-23464067-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003831.5(RIOK3):​c.280G>A​(p.Ala94Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RIOK3
NM_003831.5 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.01

Publications

0 publications found
Variant links:
Genes affected
RIOK3 (HGNC:11451): (RIO kinase 3) This gene was first identified by the similarity of its product to the Aspergillus nidulans SUDD protein. This gene is now recognized as a member of the right open reading frame (RIO) kinase gene family. This gene encodes a serine/threonine kinase that localizes to the cytoplasm and plays a role in the processing of the pre-40 S ribosomal subunit. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2017]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.14633778).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RIOK3NM_003831.5 linkc.280G>A p.Ala94Thr missense_variant Exon 3 of 13 ENST00000339486.8 NP_003822.2
RIOK3NM_001348193.2 linkc.232G>A p.Ala78Thr missense_variant Exon 3 of 13 NP_001335122.1
RIOK3XM_047437912.1 linkc.280G>A p.Ala94Thr missense_variant Exon 3 of 9 XP_047293868.1
RIOK3NR_145477.2 linkn.433G>A non_coding_transcript_exon_variant Exon 3 of 13

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RIOK3ENST00000339486.8 linkc.280G>A p.Ala94Thr missense_variant Exon 3 of 13 1 NM_003831.5 ENSP00000341874.3 O14730-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152172
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000399
AC:
1
AN:
250570
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461168
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726886
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33434
American (AMR)
AF:
0.00
AC:
0
AN:
44572
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26102
East Asian (EAS)
AF:
0.0000504
AC:
2
AN:
39682
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86122
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53414
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5758
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111730
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60354
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152172
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74328
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41446
American (AMR)
AF:
0.00
AC:
0
AN:
15270
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5194
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10608
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68032
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 27, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.280G>A (p.A94T) alteration is located in exon 3 (coding exon 3) of the RIOK3 gene. This alteration results from a G to A substitution at nucleotide position 280, causing the alanine (A) at amino acid position 94 to be replaced by a threonine (T). 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
Benign
0.070
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.045
T;.;.
Eigen
Benign
-0.086
Eigen_PC
Benign
0.18
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
D;D;D
M_CAP
Benign
0.0087
T
MetaRNN
Benign
0.15
T;T;T
MetaSVM
Benign
-0.84
T
MutationAssessor
Benign
0.52
N;.;N
PhyloP100
6.0
PrimateAI
Uncertain
0.66
T
PROVEAN
Benign
-0.24
N;.;.
REVEL
Benign
0.10
Sift
Benign
0.34
T;.;.
Sift4G
Benign
0.33
T;T;T
Polyphen
0.013
B;B;B
Vest4
0.24
MutPred
0.20
Gain of phosphorylation at A94 (P = 0.0174);.;Gain of phosphorylation at A94 (P = 0.0174);
MVP
0.37
MPC
0.31
ClinPred
0.53
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.074
gMVP
0.15
Mutation Taster
=75/25
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1410632170; hg19: chr18-21044031; API