14-91060379-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_004755.4(RPS6KA5):​c.56G>T​(p.Gly19Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000516 in 1,356,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000052 ( 0 hom. )

Consequence

RPS6KA5
NM_004755.4 missense

Scores

2
1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.24
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]
DGLUCY (HGNC:20498): (D-glutamate cyclase) Predicted to enable D-glutamate cyclase activity. Predicted to be involved in glutamate metabolic process. Predicted to be located in mitochondrial matrix. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.27975538).
BS2
High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RPS6KA5NM_004755.4 linkuse as main transcriptc.56G>T p.Gly19Val missense_variant 1/17 ENST00000614987.5 NP_004746.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RPS6KA5ENST00000614987.5 linkuse as main transcriptc.56G>T p.Gly19Val missense_variant 1/171 NM_004755.4 ENSP00000479667 P1O75582-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000169
AC:
3
AN:
177900
Hom.:
0
AF XY:
0.0000200
AC XY:
2
AN XY:
100230
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000102
Gnomad SAS exome
AF:
0.0000420
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000256
GnomAD4 exome
AF:
0.00000516
AC:
7
AN:
1356290
Hom.:
0
Cov.:
31
AF XY:
0.00000595
AC XY:
4
AN XY:
672714
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000125
Gnomad4 SAS exome
AF:
0.0000136
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000365
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000113
ExAC
AF:
0.0000167
AC:
2

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 25, 2023The c.56G>T (p.G19V) alteration is located in exon 1 (coding exon 1) of the RPS6KA5 gene. This alteration results from a G to T substitution at nucleotide position 56, causing the glycine (G) at amino acid position 19 to be replaced by a valine (V). 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
0.088
BayesDel_addAF
Benign
-0.066
T
BayesDel_noAF
Benign
-0.12
CADD
Benign
18
DANN
Uncertain
0.99
DEOGEN2
Benign
0.22
T;.
Eigen
Benign
-0.017
Eigen_PC
Benign
0.025
FATHMM_MKL
Benign
0.73
D
LIST_S2
Benign
0.70
T;T
M_CAP
Pathogenic
0.79
D
MetaRNN
Benign
0.28
T;T
MetaSVM
Benign
-0.59
T
MutationAssessor
Benign
1.1
L;L
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.85
D
PROVEAN
Benign
-0.71
.;N
REVEL
Benign
0.12
Sift
Benign
0.045
.;D
Sift4G
Benign
0.29
T;T
Polyphen
0.99
D;B
Vest4
0.32
MutPred
0.31
Gain of catalytic residue at E23 (P = 0.0165);Gain of catalytic residue at E23 (P = 0.0165);
MVP
0.66
ClinPred
0.17
T
GERP RS
3.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.14
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: rs776541777; hg19: chr14-91526723; API