Variant chr1-26554695-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_002953.4(RPS6KA1):c.713G>A(p.Gly238Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,552 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: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RPS6KA1
NM_002953.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

RPS6KA1 (HGNC:10430): (ribosomal protein S6 kinase A1) This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains 2 nonidentical kinase catalytic domains and phosphorylates various substrates, including members of the mitogen-activated kinase (MAPK) signalling pathway. The activity of this protein has been implicated in controlling cell growth and differentiation. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

RPS6KA1 links:

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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, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS6KA1	NM_002953.4 linkuse as main transcript	c.713G>A	p.Gly238Asp	missense_variant	9/22	ENST00000374168.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS6KA1	ENST00000374168.7 linkuse as main transcript	c.713G>A	p.Gly238Asp	missense_variant	9/22	1	NM_002953.4	P1	Q15418-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460552

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726322

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

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 submitter

clinical testing

Ambry Genetics

Jan 24, 2024

The c.740G>A (p.G247D) alteration is located in exon 8 (coding exon 8) of the RPS6KA1 gene. This alteration results from a G to A substitution at nucleotide position 740, causing the glycine (G) at amino acid position 247 to be replaced by an aspartic acid (D). 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

1.0

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;.;.;.;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.076

MetaRNN

Pathogenic

0.82

D;D;D;D;D

MetaSVM

Benign

-0.38

MutationAssessor

Benign

1.0

L;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.3

D;D;D;D;D

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

0.97

D;.;.;.;D

Vest4

0.87

MutPred

0.77

Loss of catalytic residue at S240 (P = 0.0709);Loss of catalytic residue at S240 (P = 0.0709);.;.;.;

MVP

0.90

MPC

1.8

ClinPred

0.99

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.94

gMVP

0.89

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over