11-64369866-C-A

Variant names:

• chr11-64369866-C-A
• rs55643628
• NM_003942.3:c.1770C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003942.3(RPS6KA4):​c.1770C>A​(p.Cys590*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,407,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C590C) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RPS6KA4 NM_003942.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.45
• Publications: 2 publications found

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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003942.3. 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
	RPS6KA4	NM_003942.3	MANE Select	c.1770C>A	p.Cys590*	stop_gained	Exon 14 of 17	NP_003933.1	O75676-1
	RPS6KA4	NM_001006944.2		c.1752C>A	p.Cys584*	stop_gained	Exon 14 of 17	NP_001006945.1	O75676-2
	RPS6KA4	NM_001300802.2		c.1749C>A	p.Cys583*	stop_gained	Exon 14 of 17	NP_001287731.1	E9PJN1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA4	ENST00000334205.9	TSL:1 MANE Select	c.1770C>A	p.Cys590*	stop_gained	Exon 14 of 17	ENSP00000333896.4	O75676-1
	RPS6KA4	ENST00000528057.5	TSL:1	c.1749C>A	p.Cys583*	stop_gained	Exon 14 of 17	ENSP00000435580.1	E9PJN1
	RPS6KA4	ENST00000969972.1		c.1929C>A	p.Cys643*	stop_gained	Exon 14 of 17	ENSP00000640031.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1407958 Hom.: 0 Cov.: 34 AF XY: 0.00000144 AC XY: 1 AN XY: 695862

African (AFR) AF: 0.00 AC: 0 AN: 31976

American (AMR) AF: 0.00 AC: 0 AN: 36710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25162

East Asian (EAS) AF: 0.00 AC: 0 AN: 36512

South Asian (SAS) AF: 0.00 AC: 0 AN: 80698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5112

European-Non Finnish (NFE) AF: 9.22e-7 AC: 1 AN: 1085150

Other (OTH) AF: 0.00 AC: 0 AN: 58246

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	31
DANN	Uncertain	0.98
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.25	N
PhyloP100		-1.4
Vest4		0.97
GERP RS		-5.3
Mutation Taster		=21/179	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs55643628; hg19: chr11-64137338;