11-64360525-A-G

Variant names:

• chr11-64360525-A-G
• rs757067643
• NM_003942.3:c.395A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003942.3(RPS6KA4):​c.395A>G​(p.Tyr132Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,460,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: RPS6KA4 NM_003942.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

Genes affected

RPS6KA4 (HGNC:10433): (ribosomal protein S6 kinase A4) This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains 2 non-identical kinase catalytic domains and phosphorylates various substrates, including CREB1 and ATF1. The encoded protein can also phosphorylate histone H3 to regulate certain inflammatory genes. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.13474646).
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KA4	NM_003942.3	c.395A>G	p.Tyr132Cys	missense_variant	Exon 4 of 17	ENST00000334205.9	NP_003933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS6KA4	ENST00000334205.9	c.395A>G	p.Tyr132Cys	missense_variant	Exon 4 of 17	1	NM_003942.3	ENSP00000333896.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000202 AC: 5 AN: 247556 AF XY: 0.00000745

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1460390 Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8 AN XY: 726366

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33452

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44596

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26104

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39650

Gnomad4 SAS exome AF: 0.000163 AC: 14 AN: 85998

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53078

Gnomad4 NFE exome AF: 9.00e-7 AC: 1 AN: 1111396

Gnomad4 Remaining exome AF: 0.0000166 AC: 1 AN: 60348

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.395A>G (p.Y132C) alteration is located in exon 4 (coding exon 4) of the RPS6KA4 gene. This alteration results from a A to G substitution at nucleotide position 395, causing the tyrosine (Y) at amino acid position 132 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	23
DANN	Benign	0.95
DEOGEN2	Benign	0.23	.;T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.075	.;N;.
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Benign	0.093
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.87	P;B;.
Vest4		0.33
MutPred		0.37		Loss of catalytic residue at L127 (P = 0.0849);Loss of catalytic residue at L127 (P = 0.0849);.;
MVP		0.42
MPC		0.54
ClinPred		0.092	T
GERP RS		3.3
Varity_R		0.21
gMVP		0.85
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs757067643; hg19: chr11-64127997;