NM_004586.3:c.2101-56T>C

Variant names:

• chrX-20155576-A-G
• rs73631381
• NM_004586.3:c.2101-56T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 publications found

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]

RPS6KA3 Gene-Disease associations (from GenCC):

• Coffin-Lowry syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet, Genomics England PanelApp
• intellectual disability, X-linked 19

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• symptomatic form of Coffin-Lowry syndrome in female carriers

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004586.3. 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
	RPS6KA3	NM_004586.3	MANE Select	c.2101-56T>C		intron	N/A	NP_004577.1	P51812
	RPS6KA3	NM_001438340.1		c.2017-56T>C		intron	N/A	NP_001425269.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA3	ENST00000379565.9	TSL:1 MANE Select	c.2101-56T>C		intron	N/A	ENSP00000368884.3	P51812
	RPS6KA3	ENST00000952699.1		c.2149-56T>C		intron	N/A	ENSP00000622758.1
	RPS6KA3	ENST00000916293.1		c.2119-56T>C		intron	N/A	ENSP00000586352.1

Frequencies

GnomAD3 genomes AF: 0.0209 AC: 2340 AN: 112039 Hom.: 56 Cov.: 23

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

African (AFR) AF: 0.0813 AC: 2053 AN: 25256

American (AMR) AF: 0.00625 AC: 219 AN: 35025

Ashkenazi Jewish (ASJ) AF: 0.00232 AC: 44 AN: 18974

East Asian (EAS) AF: 0.0000334 AC: 1 AN: 29897

South Asian (SAS) AF: 0.000247 AC: 13 AN: 52570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40241

Middle Eastern (MID) AF: 0.0120 AC: 48 AN: 3991

European-Non Finnish (NFE) AF: 0.000363 AC: 285 AN: 785841

Other (OTH) AF: 0.00676 AC: 298 AN: 44091

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

African (AFR) AF: 0.0712 AC: 2193 AN: 30812

American (AMR) AF: 0.00892 AC: 94 AN: 10537

Ashkenazi Jewish (ASJ) AF: 0.00113 AC: 3 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3587

South Asian (SAS) AF: 0.000740 AC: 2 AN: 2701

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6095

Middle Eastern (MID) AF: 0.0184 AC: 4 AN: 217

European-Non Finnish (NFE) AF: 0.000206 AC: 11 AN: 53270

Other (OTH) AF: 0.0261 AC: 40 AN: 1530

Alfa AF: 0.0271 Hom.: 413

Bravo AF: 0.0250

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.4
DANN	Benign	0.69
PhyloP100		0.33
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs73631381; hg19: chrX-20173694;