14-74907099-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_031464.5(RPS6KL1):​c.1565G>A​(p.Arg522His) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

RPS6KL1
NM_031464.5 missense

Scores

9
7
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.49
Variant links:
Genes affected
RPS6KL1 (HGNC:20222): (ribosomal protein S6 kinase like 1) Predicted to enable ATP binding activity; protein serine kinase activity; and protein serine/threonine kinase activity. Predicted to be involved in protein phosphorylation. Predicted to be located in ribosome. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RPS6KL1NM_031464.5 linkc.1565G>A p.Arg522His missense_variant Exon 12 of 12 ENST00000557413.6 NP_113652.2 Q9Y6S9-1B4DSP6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RPS6KL1ENST00000557413.6 linkc.1565G>A p.Arg522His missense_variant Exon 12 of 12 5 NM_031464.5 ENSP00000450567.1 Q9Y6S9-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000799
AC:
2
AN:
250286
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135250
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000463
Gnomad NFE exome
AF:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461046
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
726808
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00000989
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000756
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 15, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1565G>A (p.R522H) alteration is located in exon 11 (coding exon 10) of the RPS6KL1 gene. This alteration results from a G to A substitution at nucleotide position 1565, causing the arginine (R) at amino acid position 522 to be replaced by a histidine (H). 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
Pathogenic
0.79
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.20
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.29
T;T;.;T
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.77
T;.;T;.
M_CAP
Uncertain
0.12
D
MetaRNN
Pathogenic
0.98
D;D;D;D
MetaSVM
Uncertain
0.15
D
MutationAssessor
Pathogenic
3.8
H;H;.;H
PrimateAI
Uncertain
0.50
T
PROVEAN
Uncertain
-4.1
.;D;D;D
REVEL
Uncertain
0.59
Sift
Uncertain
0.0010
.;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;D;.;D
Vest4
0.91
MutPred
0.94
Loss of phosphorylation at T520 (P = 0.0815);Loss of phosphorylation at T520 (P = 0.0815);.;Loss of phosphorylation at T520 (P = 0.0815);
MVP
0.84
MPC
0.78
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.61
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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: rs756146700; hg19: chr14-75373802; API