Genetic Variant RPS6KA5:p.Gly19Asp (chr14-91060379-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004755.4(RPS6KA5):c.56G>A(p.Gly19Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,356,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G19V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

RPS6KA5
NM_004755.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.24

Publications

2 publications found

Variant links:

Genes affected

RPS6KA5 (HGNC:10434): (ribosomal protein S6 kinase A5) Enables ATP binding activity and protein serine/threonine kinase activity. Involved in several processes, including histone-serine phosphorylation; positive regulation of histone modification; and regulation of transcription, DNA-templated. Located in cytoplasm and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

RPS6KA5 links:

DGLUCY (HGNC:20498): (D-glutamate cyclase) Predicted to enable D-glutamate cyclase activity. Predicted to be involved in glutamate metabolic process. Predicted to be located in mitochondrial matrix. [provided by Alliance of Genome Resources, Apr 2022]

DGLUCY links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17133936).

BS2

High AC in GnomAdExome4 at 15 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004755.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RPS6KA5	NM_004755.4	MANE Select	c.56G>A	p.Gly19Asp	missense	Exon 1 of 17	NP_004746.2
RPS6KA5	NM_001322229.2		c.56G>A	p.Gly19Asp	missense	Exon 1 of 17	NP_001309158.1
RPS6KA5	NM_001322236.2		c.56G>A	p.Gly19Asp	missense	Exon 1 of 16	NP_001309165.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPS6KA5	ENST00000614987.5	TSL:1 MANE Select	c.56G>A	p.Gly19Asp	missense	Exon 1 of 17	ENSP00000479667.1	O75582-1
RPS6KA5	ENST00000418736.6	TSL:1	c.56G>A	p.Gly19Asp	missense	Exon 1 of 13	ENSP00000402787.2	O75582-2
RPS6KA5	ENST00000554206.1	TSL:1	n.56G>A		non_coding_transcript_exon	Exon 1 of 10	ENSP00000450591.1	G3V2D1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000562

AC:

AN:

177900

AF XY:

0.0000299

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000358

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:

0.000256

GnomAD4 exome

AF:

0.0000111

AC:

AN:

1356290

Hom.:

Cov.:

AF XY:

0.00000743

AC XY:

AN XY:

672714

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28534

American (AMR)

AF:

0.000339

AC:

AN:

35380

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23476

East Asian (EAS)

AF:

0.00

AC:

AN:

32068

South Asian (SAS)

AF:

0.00

AC:

AN:

73790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48186

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5338

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1054676

Other (OTH)

AF:

0.0000547

AC:

AN:

54842

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

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.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000167

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.16

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.66

M_CAP

Pathogenic

0.53

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.34

PhyloP100

3.2

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

0.42

REVEL

Benign

0.16

Sift

Benign

0.91

Sift4G

Benign

0.97

Polyphen

0.99

Vest4

0.35

MutPred

0.24

Gain of catalytic residue at E23 (P = 0.0283)

MVP

0.78

ClinPred

0.11

GERP RS

3.0

PromoterAI

0.064

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over