X-20155576-A-G

Position:

• chrX-20155576-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004586.3(RPS6KA3):​c.2101-56T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00462 in 1,147,978 control chromosomes in the GnomAD database, including 133 homozygotes. There are 1,400 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (57 hom., 648 hem., cov: 23)
  • Exomes 𝑓: 0.0029 (76 hom. 752 hem.)
• Consequence: RPS6KA3 NM_004586.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.330

Genes affected

RPS6KA3 (HGNC:10432): (ribosomal protein S6 kinase A3) 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 members of the mitogen-activated kinase (MAPK) signalling pathway. The activity of this protein has been implicated in controlling cell growth and differentiation. Mutations in this gene have been associated with Coffin-Lowry syndrome (CLS). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-20155576-A-G is Benign according to our data. Variant chrX-20155576-A-G is described in ClinVar as [Benign]. Clinvar id is 1275092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0687 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS6KA3	NM_004586.3	c.2101-56T>C		intron_variant		ENST00000379565.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS6KA3	ENST00000379565.9	c.2101-56T>C		intron_variant		1	NM_004586.3	P4

Frequencies

GnomAD3 genomes AF: 0.0209 AC: 2340 AN: 112039 Hom.: 56 Cov.: 23 AF XY: 0.0189 AC XY: 645 AN XY: 34197

Gnomad AFR AF: 0.0711

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00893

Gnomad ASJ AF: 0.00113

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000738

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0210

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0265

GnomAD4 exome AF: 0.00286 AC: 2961 AN: 1035886 Hom.: 76 AF XY: 0.00243 AC XY: 752 AN XY: 309486

Gnomad4 AFR exome AF: 0.0813

Gnomad4 AMR exome AF: 0.00625

Gnomad4 ASJ exome AF: 0.00232

Gnomad4 EAS exome AF: 0.0000334

Gnomad4 SAS exome AF: 0.000247

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000363

Gnomad4 OTH exome AF: 0.00676

GnomAD4 genome AF: 0.0209 AC: 2347 AN: 112092 Hom.: 57 Cov.: 23 AF XY: 0.0189 AC XY: 648 AN XY: 34260

Gnomad4 AFR AF: 0.0712

Gnomad4 AMR AF: 0.00892

Gnomad4 ASJ AF: 0.00113

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000740

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0261

Alfa AF: 0.0118 Hom.: 57

Bravo AF: 0.0250

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.4
DANN	Benign	0.69

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: rs73631381; hg19: chrX-20173694;