Genetic Variant RPS6KA6:p.Ile412Val (chrX-84106918-T-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_014496.5(RPS6KA6):c.1234A>G(p.Ile412Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,176,075 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000018 ( 0 hom. 11 hem. )

Consequence

RPS6KA6
NM_014496.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.22

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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03964269).

BS2

High Hemizygotes in GnomAd4 at 2 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.1234A>G	p.Ile412Val	missense	Exon 14 of 22	NP_055311.1	Q9UK32-1
	RPS6KA6	NM_001330512.1		c.1234A>G	p.Ile412Val	missense	Exon 16 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.1234A>G	p.Ile412Val	missense	Exon 14 of 22	ENSP00000262752.2	Q9UK32-1
RPS6KA6	ENST00000620340.4	TSL:5	c.1234A>G	p.Ile412Val	missense	Exon 14 of 22	ENSP00000483896.1	Q9UK32-2
RPS6KA6	ENST00000911420.1		c.1234A>G	p.Ile412Val	missense	Exon 14 of 22	ENSP00000581479.1

Frequencies

GnomAD3 genomes

AF:

0.0000447

AC:

AN:

111844

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000130

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:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000420

AC:

AN:

166693

AF XY:

0.0000553

show subpopulations

Gnomad AFR exome

AF:

0.000160

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:

0.0000654

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000179

AC:

AN:

1064179

Hom.:

Cov.:

AF XY:

0.0000326

AC XY:

AN XY:

337053

show subpopulations

African (AFR)

AF:

0.000235

AC:

AN:

25567

American (AMR)

AF:

0.00

AC:

AN:

32488

Ashkenazi Jewish (ASJ)

AF:

0.000107

AC:

AN:

18701

East Asian (EAS)

AF:

0.0000338

AC:

AN:

29580

South Asian (SAS)

AF:

0.00

AC:

AN:

49333

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40078

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3987

European-Non Finnish (NFE)

AF:

0.0000110

AC:

AN:

819582

Other (OTH)

AF:

0.0000223

AC:

AN:

44863

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

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:

0.0000447

AC:

AN:

111896

Hom.:

Cov.:

AF XY:

0.0000587

AC XY:

AN XY:

34090

show subpopulations

African (AFR)

AF:

0.000129

AC:

AN:

30923

American (AMR)

AF:

0.00

AC:

AN:

10519

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3561

South Asian (SAS)

AF:

0.00

AC:

AN:

2731

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6093

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

52998

Other (OTH)

AF:

0.00

AC:

AN:

1523

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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:

0.0000868

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

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

0.058

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.62

CADD

Benign

8.4

(source)

DANN

Benign

0.43

DEOGEN2

Benign

0.088

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.73

M_CAP

Benign

0.018

MetaRNN

Benign

0.040

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

1.2

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.25

REVEL

Benign

0.052

Sift

Benign

1.0

Sift4G

Benign

0.82

Polyphen

0.0060

Vest4

0.098

MVP

0.59

MPC

0.43

ClinPred

0.020

GERP RS

2.6

Varity_R

0.069

gMVP

0.23

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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