Genetic Variant RPS6KA6:p.Ala180Ser (chrX-84135174-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_014496.5(RPS6KA6):c.538G>T(p.Ala180Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000574 in 1,201,101 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 21 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000060 ( 0 hom. 21 hem. )

Consequence

RPS6KA6
NM_014496.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.73

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 -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 21 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.538G>T	p.Ala180Ser	missense	Exon 7 of 22	NP_055311.1	Q9UK32-1
	RPS6KA6	NM_001330512.1		c.538G>T	p.Ala180Ser	missense	Exon 9 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.538G>T	p.Ala180Ser	missense	Exon 7 of 22	ENSP00000262752.2	Q9UK32-1
RPS6KA6	ENST00000620340.4	TSL:5	c.538G>T	p.Ala180Ser	missense	Exon 7 of 22	ENSP00000483896.1	Q9UK32-2
RPS6KA6	ENST00000911420.1		c.538G>T	p.Ala180Ser	missense	Exon 7 of 22	ENSP00000581479.1

Frequencies

GnomAD3 genomes

AF:

0.0000359

AC:

AN:

111342

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:

0.0000757

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000339

AC:

AN:

177110

AF XY:

0.0000160

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:

0.0000764

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000596

AC:

AN:

1089759

Hom.:

Cov.:

AF XY:

0.0000590

AC XY:

AN XY:

356233

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26189

American (AMR)

AF:

0.00

AC:

AN:

34941

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19245

East Asian (EAS)

AF:

0.0000334

AC:

AN:

29940

South Asian (SAS)

AF:

0.00

AC:

AN:

53273

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4110

European-Non Finnish (NFE)

AF:

0.0000742

AC:

AN:

835968

Other (OTH)

AF:

0.0000437

AC:

AN:

45717

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

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:

0.0000359

AC:

AN:

111342

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33612

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30748

American (AMR)

AF:

0.00

AC:

AN:

10433

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.00

AC:

AN:

3566

South Asian (SAS)

AF:

0.00

AC:

AN:

2683

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

235

European-Non Finnish (NFE)

AF:

0.0000757

AC:

AN:

52849

Other (OTH)

AF:

0.00

AC:

AN:

1492

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.0000302

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions as Germline

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

Uncertain

0.38

BayesDel_addAF

Benign

-0.026

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.025

MetaRNN

Uncertain

0.44

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.6

PhyloP100

7.7

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.35

Sift

Uncertain

0.0050

Sift4G

Benign

0.082

Polyphen

0.97

Vest4

0.71

MVP

0.64

MPC

1.4

ClinPred

0.60

GERP RS

4.8

Varity_R

0.85

gMVP

0.74

Mutation Taster

=96/4

polymorphism

(source)

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

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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