1-26557097-A-C

Variant names:

• chr1-26557097-A-C
• rs779910630
• NM_002953.4:c.1081A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002953.4(RPS6KA1):​c.1081A>C​(p.Lys361Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. K361E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RPS6KA1 NM_002953.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.89
• Publications: 0 publications found

Genes affected

RPS6KA1 (HGNC:10430): (ribosomal protein S6 kinase A1) This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains 2 nonidentical kinase catalytic domains and phosphorylates various substrates, including members of the mitogen-activated kinase (MAPK) signalling pathway. The activity of this protein has been implicated in controlling cell growth and differentiation. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2640175).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002953.4. 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
	RPS6KA1	NM_002953.4	MANE Select	c.1081A>C	p.Lys361Gln	missense	Exon 13 of 22	NP_002944.2
	RPS6KA1	NM_001006665.2		c.1108A>C	p.Lys370Gln	missense	Exon 12 of 21	NP_001006666.1	Q15418-2
	RPS6KA1	NM_001330441.2		c.1033A>C	p.Lys345Gln	missense	Exon 12 of 21	NP_001317370.1	Q15418-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA1	ENST00000374168.7	TSL:1 MANE Select	c.1081A>C	p.Lys361Gln	missense	Exon 13 of 22	ENSP00000363283.2	Q15418-1
	RPS6KA1	ENST00000531382.5	TSL:2	c.1108A>C	p.Lys370Gln	missense	Exon 12 of 21	ENSP00000435412.1	Q15418-2
	RPS6KA1	ENST00000952528.1		c.1081A>C	p.Lys361Gln	missense	Exon 13 of 22	ENSP00000622587.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456422 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724862

African (AFR) AF: 0.0000300 AC: 1 AN: 33374

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107214

Other (OTH) AF: 0.00 AC: 0 AN: 60238

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.3	L
PhyloP100		5.9
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.11
Sift	Benign	0.14	T
Sift4G	Benign	0.57	T
Polyphen		0.28	B
Vest4		0.26
MutPred		0.43		Loss of ubiquitination at K361 (P = 0.002)
MVP		0.35
MPC		1.1
ClinPred		0.72	D
GERP RS		5.5
PromoterAI		-0.048	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.24
gMVP		0.50
Mutation Taster		=50/50

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

Other links and lift over

dbSNP: rs779910630; hg19: chr1-26883588;