Genetic Variant RPS6KA6:p.Ile523Met (chrX-84104544-T-C) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_014496.5(RPS6KA6):c.1569A>G(p.Ile523Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,183,077 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. 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: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000016 ( 0 hom. 5 hem. )

Consequence

RPS6KA6
NM_014496.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.825

Publications

0 publications found

Variant links:

Genes affected

RPS6KA6 (HGNC:10435): (ribosomal protein S6 kinase A6) This gene encodes a member of ribosomal S6 kinase family, serine-threonine protein kinases which are regulated by growth factors. The encoded protein may be distinct from other members of this family, however, as studies suggest it is not growth factor dependent and may not participate in the same signaling pathways. [provided by RefSeq, Jan 2010]

RPS6KA6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2875893).

BS2

High Hemizygotes in GnomAdExome4 at 5 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014496.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA6	NM_014496.5	MANE Select	c.1569A>G	p.Ile523Met	missense	Exon 17 of 22	NP_055311.1	Q9UK32-1
	RPS6KA6	NM_001330512.1		c.1569A>G	p.Ile523Met	missense	Exon 19 of 24	NP_001317441.1	Q9UK32-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPS6KA6	ENST00000262752.5	TSL:1 MANE Select	c.1569A>G	p.Ile523Met	missense	Exon 17 of 22	ENSP00000262752.2	Q9UK32-1
RPS6KA6	ENST00000620340.4	TSL:5	c.1569A>G	p.Ile523Met	missense	Exon 17 of 22	ENSP00000483896.1	Q9UK32-2
RPS6KA6	ENST00000911420.1		c.1569A>G	p.Ile523Met	missense	Exon 17 of 22	ENSP00000581479.1

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

110913

Hom.:

Cov.:

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000381

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

167759

AF XY:

0.0000180

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:

0.0000260

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000159

AC:

AN:

1072164

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

344164

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25699

American (AMR)

AF:

0.00

AC:

AN:

32887

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18701

East Asian (EAS)

AF:

0.00

AC:

AN:

29461

South Asian (SAS)

AF:

0.00

AC:

AN:

49768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39836

Middle Eastern (MID)

AF:

0.000249

AC:

AN:

4024

European-Non Finnish (NFE)

AF:

0.0000193

AC:

AN:

826894

Other (OTH)

AF:

0.00

AC:

AN:

44894

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0000180

AC:

AN:

110913

Hom.:

Cov.:

AF XY:

0.0000300

AC XY:

AN XY:

33311

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30657

American (AMR)

AF:

0.00

AC:

AN:

10427

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2634

East Asian (EAS)

AF:

0.00

AC:

AN:

3558

South Asian (SAS)

AF:

0.00

AC:

AN:

2667

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6024

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.0000381

AC:

AN:

52544

Other (OTH)

AF:

0.00

AC:

AN:

1481

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000367

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

FATHMM_MKL

Benign

0.19

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.024

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.72

MutationAssessor

Uncertain

2.3

PhyloP100

-0.82

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.8

REVEL

Benign

0.14

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.54

Vest4

0.37

MVP

0.35

MPC

1.4

ClinPred

0.76

GERP RS

0.14

Varity_R

0.60

gMVP

0.48

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over