1-213077718-G-A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001349648.2(RPS6KC1):​c.-449G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,485,736 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 33)
Exomes 𝑓: 0.000011 ( 1 hom. )

Consequence

RPS6KC1
NM_001349648.2 5_prime_UTR_premature_start_codon_gain

Scores

4
4
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.07
Variant links:
Genes affected
RPS6KC1 (HGNC:10439): (ribosomal protein S6 kinase C1) Sphingosine kinase catalyzes the formation of sphingosine 1 phosphate, a lipid cellular messenger. The protein encoded by this gene can bind to sphingosine kinase and to phosphatidylinositol 3-phosphate, suggesting a role in sphingosine 1 phophate signaling. The encoded protein can also bind to peroxiredoxin-3 and may help transport it to mitochondria. [provided by RefSeq, Mar 2017]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.4110507).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RPS6KC1NM_012424.6 linkc.164G>A p.Ser55Asn missense_variant Exon 3 of 15 ENST00000366960.8 NP_036556.2 Q96S38-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RPS6KC1ENST00000366960.8 linkc.164G>A p.Ser55Asn missense_variant Exon 3 of 15 1 NM_012424.6 ENSP00000355927.3 Q96S38-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152138
Hom.:
0
Cov.:
33
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:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000134
AC:
3
AN:
223880
AF XY:
0.0000165
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000112
AC:
15
AN:
1333598
Hom.:
1
Cov.:
23
AF XY:
0.0000165
AC XY:
11
AN XY:
666188
show subpopulations
Gnomad4 AFR exome
AF:
0.00
AC:
0
AN:
30128
Gnomad4 AMR exome
AF:
0.00
AC:
0
AN:
38302
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
24642
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
37056
Gnomad4 SAS exome
AF:
0.000209
AC:
15
AN:
71940
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
51986
Gnomad4 NFE exome
AF:
0.00
AC:
0
AN:
1018566
Gnomad4 Remaining exome
AF:
0.00
AC:
0
AN:
55476
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
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:
152138
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.00
AC:
0
AN:
0
Gnomad4 AMR
AF:
0.00
AC:
0
AN:
0
Gnomad4 ASJ
AF:
0.00
AC:
0
AN:
0
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.000207
AC:
0.000207125
AN:
0.000207125
Gnomad4 FIN
AF:
0.00
AC:
0
AN:
0
Gnomad4 NFE
AF:
0.00
AC:
0
AN:
0
Gnomad4 OTH
AF:
0.00
AC:
0
AN:
0
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
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
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Mar 14, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; 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. This variant has not been reported in the literature in individuals affected with RPS6KC1-related conditions. This variant is present in population databases (rs774349575, gnomAD 0.01%). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 55 of the RPS6KC1 protein (p.Ser55Asn). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.72
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.50
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.011
T;.
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.93
D;D
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.41
T;T
MetaSVM
Benign
-0.66
T
MutationAssessor
Benign
1.9
L;.
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-1.2
N;N
REVEL
Benign
0.22
Sift
Benign
0.23
T;T
Sift4G
Uncertain
0.021
D;D
Polyphen
1.0
D;.
Vest4
0.52
MutPred
0.64
Gain of relative solvent accessibility (P = 0.09);.;
MVP
0.66
MPC
0.35
ClinPred
0.70
D
GERP RS
5.6
Varity_R
0.30
gMVP
0.69
Mutation Taster
=58/42
polymorphism

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: rs774349575; hg19: chr1-213251060; API