Genetic Variant RPS6KL1:p.Ala482Ser (chr14-74907530-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_031464.5(RPS6KL1):c.1444G>T(p.Ala482Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,417,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A482E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RPS6KL1
NM_031464.5 missense, splice_region

Scores

Splicing: ADA: 0.9993

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.00

Publications

0 publications found

Variant links:

Genes affected

RPS6KL1 (HGNC:20222): (ribosomal protein S6 kinase like 1) Predicted to enable ATP binding activity; protein serine kinase activity; and protein serine/threonine kinase activity. Predicted to be involved in protein phosphorylation. Predicted to be located in ribosome. [provided by Alliance of Genome Resources, Apr 2022]

RPS6KL1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031464.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPS6KL1	NM_031464.5	MANE Select	c.1444G>T	p.Ala482Ser	missense splice_region	Exon 11 of 12	NP_113652.2	Q9Y6S9-1
RPS6KL1	NM_001370252.1		c.1444G>T	p.Ala482Ser	missense splice_region	Exon 10 of 11	NP_001357181.1
RPS6KL1	NM_001370253.1		c.1399G>T	p.Ala467Ser	missense splice_region	Exon 11 of 11	NP_001357182.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPS6KL1	ENST00000557413.6	TSL:5 MANE Select	c.1444G>T	p.Ala482Ser	missense splice_region	Exon 11 of 12	ENSP00000450567.1	Q9Y6S9-1
RPS6KL1	ENST00000555009.5	TSL:1	n.1351G>T		splice_region non_coding_transcript_exon	Exon 9 of 12	ENSP00000450660.1	Q9Y6S9-2
RPS6KL1	ENST00000553315.1	TSL:3	c.1G>T	p.Ala1Ser	missense	Exon 1 of 2	ENSP00000450968.1	H0YJ80

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000226

AC:

AN:

177302

AF XY:

0.0000212

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000149

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:

0.00000212

AC:

AN:

1417632

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

700584

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32658

American (AMR)

AF:

0.0000787

AC:

AN:

38124

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25350

East Asian (EAS)

AF:

0.00

AC:

AN:

37680

South Asian (SAS)

AF:

0.00

AC:

AN:

80558

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49760

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1089056

Other (OTH)

AF:

0.00

AC:

AN:

58736

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

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

0.086

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0012

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.85

M_CAP

Benign

0.0085

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.56

PhyloP100

3.0

PrimateAI

Benign

0.42

PROVEAN

Benign

0.64

REVEL

Benign

0.10

Sift

Benign

0.50

Sift4G

Benign

0.68

Polyphen

0.0090

Vest4

0.25

MutPred

0.41

Gain of disorder (P = 0.0212)

MVP

0.45

MPC

0.16

ClinPred

0.11

GERP RS

4.7

PromoterAI

0.0058

Neutral

(source)

Varity_R

0.089

gMVP

0.21

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

SpliceAI score (max)

0.33

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.33

Position offset: 0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over