14-90875205-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_004755.4(RPS6KA5):​c.1992C>G​(p.Ile664Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,638 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: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RPS6KA5
NM_004755.4 missense

Scores

1
8
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.591
Variant links:
Genes affected
RPS6KA5 (HGNC:10434): (ribosomal protein S6 kinase A5) Enables ATP binding activity and protein serine/threonine kinase activity. Involved in several processes, including histone-serine phosphorylation; positive regulation of histone modification; and regulation of transcription, DNA-templated. Located in cytoplasm and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.805

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RPS6KA5NM_004755.4 linkc.1992C>G p.Ile664Met missense_variant Exon 15 of 17 ENST00000614987.5 NP_004746.2 O75582-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RPS6KA5ENST00000614987.5 linkc.1992C>G p.Ile664Met missense_variant Exon 15 of 17 1 NM_004755.4 ENSP00000479667.1 O75582-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.0000160
AC:
4
AN:
249500
Hom.:
0
AF XY:
0.0000297
AC XY:
4
AN XY:
134894
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000219
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:
0.00000137
AC:
2
AN:
1459638
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
726190
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
Bravo
AF:
0.00000756
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
Dec 03, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1992C>G (p.I664M) alteration is located in exon 15 (coding exon 15) of the RPS6KA5 gene. This alteration results from a C to G substitution at nucleotide position 1992, causing the isoleucine (I) at amino acid position 664 to be replaced by a methionine (M). 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
Uncertain
0.56
BayesDel_addAF
Benign
-0.074
T
BayesDel_noAF
Uncertain
-0.050
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Benign
0.17
T;.
Eigen
Benign
0.047
Eigen_PC
Benign
0.030
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Benign
0.027
D
MetaRNN
Pathogenic
0.81
D;D
MetaSVM
Benign
-0.64
T
MutationAssessor
Uncertain
2.3
M;.
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-1.4
.;N
REVEL
Uncertain
0.47
Sift
Benign
0.062
.;T
Sift4G
Benign
0.095
T;T
Polyphen
0.54
P;.
Vest4
0.81
MutPred
0.74
Gain of disorder (P = 0.0443);.;
MVP
0.90
ClinPred
0.22
T
GERP RS
0.61
Varity_R
0.75
gMVP
0.67

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: rs767594984; hg19: chr14-91341549; API