1-26546876-G-C

Variant names:

• chr1-26546876-G-C
• rs778579909
• NM_002953.4:c.118G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002953.4(RPS6KA1):​c.118G>C​(p.Val40Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. V40I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RPS6KA1 NM_002953.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.670
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02817458).

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.118G>C	p.Val40Leu	missense	Exon 3 of 22	NP_002944.2
	RPS6KA1	NM_001006665.2		c.145G>C	p.Val49Leu	missense	Exon 2 of 21	NP_001006666.1	Q15418-2
	RPS6KA1	NM_001330441.2		c.70G>C	p.Val24Leu	missense	Exon 2 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.118G>C	p.Val40Leu	missense	Exon 3 of 22	ENSP00000363283.2	Q15418-1
	RPS6KA1	ENST00000531382.5	TSL:2	c.145G>C	p.Val49Leu	missense	Exon 2 of 21	ENSP00000435412.1	Q15418-2
	RPS6KA1	ENST00000952528.1		c.118G>C	p.Val40Leu	missense	Exon 3 of 22	ENSP00000622587.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461554 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727092

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111772

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.37
DANN	Benign	0.73
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.19	N
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.67
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.12
Sift	Benign	0.71	T
Sift4G	Benign	0.70	T
Polyphen		0.0010	B
Vest4		0.16
MutPred		0.15		Loss of methylation at K42 (P = 0.0693)
MVP		0.51
MPC		0.59
ClinPred		0.028	T
GERP RS		-5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.023
gMVP		0.24
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs778579909; hg19: chr1-26873367;