chr1-26557020-A-G

Variant names:

• chr1-26557020-A-G
• rs2229712
• NM_002953.4:c.1004A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002953.4(RPS6KA1):​c.1004A>G​(p.Lys335Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPS6KA1 NM_002953.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.21
• Publications: 38 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23405194).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA1	NM_002953.4	MANE Select	c.1004A>G	p.Lys335Arg	missense	Exon 13 of 22	NP_002944.2
	RPS6KA1	NM_001006665.2		c.1031A>G	p.Lys344Arg	missense	Exon 12 of 21	NP_001006666.1
	RPS6KA1	NM_001330441.2		c.956A>G	p.Lys319Arg	missense	Exon 12 of 21	NP_001317370.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA1	ENST00000374168.7	TSL:1 MANE Select	c.1004A>G	p.Lys335Arg	missense	Exon 13 of 22	ENSP00000363283.2
	RPS6KA1	ENST00000531382.5	TSL:2	c.1031A>G	p.Lys344Arg	missense	Exon 12 of 21	ENSP00000435412.1
	RPS6KA1	ENST00000374166.8	TSL:5	c.971A>G	p.Lys324Arg	missense	Exon 13 of 22	ENSP00000363281.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.091
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.74	N
PhyloP100		7.2
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.11
Sift	Benign	0.49	T
Sift4G	Benign	0.54	T
Polyphen		0.46	P
Vest4		0.37
MutPred		0.29		Loss of methylation at K335 (P = 0.0081)
MVP		0.66
MPC		0.50
ClinPred		0.61	D
GERP RS		5.5
PromoterAI		-0.0088	Neutral
Varity_R		0.43
gMVP		0.43
Mutation Taster		=67/33	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

Other links and lift over

dbSNP: rs2229712; hg19: chr1-26883511;