chr11-64368572-G-A

Position:

• chr11-64368572-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_003942.3(RPS6KA4):​c.1305G>A​(p.Gln435=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00266 in 1,600,408 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (9 hom.)
• Consequence: RPS6KA4 NM_003942.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0130

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]

MIR1237 (HGNC:33927): (microRNA 1237) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 11-64368572-G-A is Benign according to our data. Variant chr11-64368572-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2641923.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.013 with no splicing effect.
• BS2: High AC in GnomAd4 at 257 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS6KA4	NM_003942.3	c.1305G>A	p.Gln435=	synonymous_variant	11/17	ENST00000334205.9
MIR1237	NR_031602.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS6KA4	ENST00000334205.9	c.1305G>A	p.Gln435=	synonymous_variant	11/17	1	NM_003942.3	P1
MIR1237	ENST00000408346.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 257 AN: 152186 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00325

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00159 AC: 354 AN: 222886 Hom.: 0 AF XY: 0.00159 AC XY: 193 AN XY: 121574

Gnomad AFR exome AF: 0.000150

Gnomad AMR exome AF: 0.000402

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000998

Gnomad NFE exome AF: 0.00314

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00277 AC: 4007 AN: 1448104 Hom.: 9 Cov.: 39 AF XY: 0.00275 AC XY: 1977 AN XY: 719218

Gnomad4 AFR exome AF: 0.000569

Gnomad4 AMR exome AF: 0.000511

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.0000238

Gnomad4 FIN exome AF: 0.00145

Gnomad4 NFE exome AF: 0.00341

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00169 AC: 257 AN: 152304 Hom.: 1 Cov.: 33 AF XY: 0.00134 AC XY: 100 AN XY: 74490

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00325

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00183 Hom.: 0

Bravo AF: 0.00173

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

RPS6KA4: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.1
DANN	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs144214742; hg19: chr11-64136044;