Genetic Variant NM_014496.5:c.1843A>G (chrX-84097782-T-C) – 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.1843A>G(p.Met615Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000152 in 1,181,151 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 23)

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: 7.79

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 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.1843A>G	p.Met615Val	missense	Exon 19 of 22	NP_055311.1	Q9UK32-1
	RPS6KA6	NM_001330512.1		c.1843A>G	p.Met615Val	missense	Exon 21 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.1843A>G	p.Met615Val	missense	Exon 19 of 22	ENSP00000262752.2	Q9UK32-1
RPS6KA6	ENST00000620340.4	TSL:5	c.1843A>G	p.Met615Val	missense	Exon 19 of 22	ENSP00000483896.1	Q9UK32-2
RPS6KA6	ENST00000911420.1		c.1843A>G	p.Met615Val	missense	Exon 19 of 22	ENSP00000581479.1

Frequencies

GnomAD3 genomes

AF:

0.00000902

AC:

AN:

110908

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:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000113

AC:

AN:

176972

AF XY:

0.0000161

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000767

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000159

AC:

AN:

1070243

Hom.:

Cov.:

AF XY:

0.0000147

AC XY:

AN XY:

340235

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25821

American (AMR)

AF:

0.0000865

AC:

AN:

34671

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19055

East Asian (EAS)

AF:

0.00

AC:

AN:

29878

South Asian (SAS)

AF:

0.00

AC:

AN:

52188

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4068

European-Non Finnish (NFE)

AF:

0.0000159

AC:

AN:

819151

Other (OTH)

AF:

0.0000222

AC:

AN:

45063

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.00000902

AC:

AN:

110908

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33310

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30742

American (AMR)

AF:

0.00

AC:

AN:

10326

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2634

East Asian (EAS)

AF:

0.00

AC:

AN:

3556

South Asian (SAS)

AF:

0.00

AC:

AN:

2648

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5984

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

52604

Other (OTH)

AF:

0.00

AC:

AN:

1494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.0000340

ExAC

AF:

0.00000824

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

0.29

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.54

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.88

PhyloP100

7.8

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.42

Sift

Uncertain

0.010

Sift4G

Benign

0.073

Polyphen

0.45

Vest4

0.62

MutPred

0.57

Gain of catalytic residue at M615 (P = 0.0778)

MVP

0.95

MPC

1.1

ClinPred

0.65

GERP RS

5.5

Varity_R

0.69

gMVP

0.87

Mutation Taster

=90/10

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