NM_003942.3:c.1770C>T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_003942.3(RPS6KA4):​c.1770C>T​(p.Cys590Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,560,258 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0071 (15 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (33 hom.)
• Consequence: RPS6KA4 NM_003942.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 11-64369866-C-T is Benign according to our data. Variant chr11-64369866-C-T is described in ClinVar as Benign. ClinVar VariationId is 776621.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.45 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00708 (1079/152300) while in subpopulation AFR AF = 0.0243 (1009/41568). AF 95% confidence interval is 0.023. There are 15 homozygotes in GnomAd4. There are 489 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1079 AD gene.

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>T	p.Cys590Cys	synonymous	Exon 14 of 17	NP_003933.1	O75676-1
	RPS6KA4	NM_001006944.2		c.1752C>T	p.Cys584Cys	synonymous	Exon 14 of 17	NP_001006945.1	O75676-2
	RPS6KA4	NM_001300802.2		c.1749C>T	p.Cys583Cys	synonymous	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>T	p.Cys590Cys	synonymous	Exon 14 of 17	ENSP00000333896.4	O75676-1
	RPS6KA4	ENST00000528057.5	TSL:1	c.1749C>T	p.Cys583Cys	synonymous	Exon 14 of 17	ENSP00000435580.1	E9PJN1
	RPS6KA4	ENST00000969972.1		c.1929C>T	p.Cys643Cys	synonymous	Exon 14 of 17	ENSP00000640031.1

Frequencies

GnomAD3 genomes AF: 0.00706 AC: 1074 AN: 152182 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00288 AC: 460 AN: 159514 AF XY: 0.00294

Gnomad AFR exome AF: 0.0249

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000489

Gnomad OTH exome AF: 0.000913

GnomAD4 exome AF: 0.00128 AC: 1805 AN: 1407958 Hom.: 33 Cov.: 34 AF XY: 0.00140 AC XY: 976 AN XY: 695862

African (AFR) AF: 0.0282 AC: 902 AN: 31976

American (AMR) AF: 0.00147 AC: 54 AN: 36710

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

East Asian (EAS) AF: 0.0000274 AC: 1 AN: 36512

South Asian (SAS) AF: 0.00833 AC: 672 AN: 80698

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

Middle Eastern (MID) AF: 0.00137 AC: 7 AN: 5112

European-Non Finnish (NFE) AF: 0.0000184 AC: 20 AN: 1085150

Other (OTH) AF: 0.00256 AC: 149 AN: 58246

GnomAD4 genome AF: 0.00708 AC: 1079 AN: 152300 Hom.: 15 Cov.: 33 AF XY: 0.00657 AC XY: 489 AN XY: 74484

African (AFR) AF: 0.0243 AC: 1009 AN: 41568

American (AMR) AF: 0.00144 AC: 22 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00642 AC: 31 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68026

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00225 Hom.: 1

Bravo AF: 0.00753

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	9.6
DANN	Benign	0.93
PhyloP100		-1.4
Mutation Taster		=100/0	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: rs55643628; hg19: chr11-64137338; COSMIC: COSV105129406; COSMIC: COSV105129406;