X-20155127-A-G

Variant names:

• chrX-20155127-A-G
• rs112566025
• NM_004586.3:c.*271T>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.*271T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 363,493 control chromosomes in the GnomAD database, including 125 homozygotes. There are 954 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (96 hom., 752 hem., cov: 23)
  • Exomes 𝑓: 0.0034 (29 hom. 202 hem.)
• Consequence: RPS6KA3 NM_004586.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.582
• Publications: 0 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=-0.51).
• BP6: Variant X-20155127-A-G is Benign according to our data. Variant chrX-20155127-A-G is described in ClinVar as Benign. ClinVar VariationId is 1248010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0839 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.*271T>C		3_prime_UTR	Exon 22 of 22	NP_004577.1	P51812
	RPS6KA3	NM_001438340.1		c.*271T>C		3_prime_UTR	Exon 22 of 22	NP_001425269.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA3	ENST00000379565.9	TSL:1 MANE Select	c.*271T>C		3_prime_UTR	Exon 22 of 22	ENSP00000368884.3	P51812
	RPS6KA3	ENST00000952699.1		c.*271T>C		3_prime_UTR	Exon 23 of 23	ENSP00000622758.1
	RPS6KA3	ENST00000916293.1		c.*271T>C		3_prime_UTR	Exon 22 of 22	ENSP00000586352.1

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 2771 AN: 112070 Hom.: 96 Cov.: 23

Gnomad AFR AF: 0.0861

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00828

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.000188

Gnomad OTH AF: 0.0159

GnomAD4 exome AF: 0.00343 AC: 862 AN: 251371 Hom.: 29 Cov.: 0 AF XY: 0.00263 AC XY: 202 AN XY: 76761

African (AFR) AF: 0.0836 AC: 657 AN: 7855

American (AMR) AF: 0.00487 AC: 57 AN: 11702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7397

East Asian (EAS) AF: 0.00 AC: 0 AN: 15800

South Asian (SAS) AF: 0.000194 AC: 5 AN: 25817

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15194

Middle Eastern (MID) AF: 0.00202 AC: 2 AN: 988

European-Non Finnish (NFE) AF: 0.000145 AC: 22 AN: 151590

Other (OTH) AF: 0.00792 AC: 119 AN: 15028

GnomAD4 genome AF: 0.0249 AC: 2793 AN: 112122 Hom.: 96 Cov.: 23 AF XY: 0.0219 AC XY: 752 AN XY: 34302

African (AFR) AF: 0.0866 AC: 2671 AN: 30842

American (AMR) AF: 0.00827 AC: 87 AN: 10526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3614

South Asian (SAS) AF: 0.00 AC: 0 AN: 2720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6098

Middle Eastern (MID) AF: 0.00457 AC: 1 AN: 219

European-Non Finnish (NFE) AF: 0.000188 AC: 10 AN: 53233

Other (OTH) AF: 0.0157 AC: 24 AN: 1530

Alfa AF: 0.0113 Hom.: 61

Bravo AF: 0.0282

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	-0.51
CADD	Benign	10
DANN	Benign	0.86
PhyloP100		0.58
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: rs112566025; hg19: chrX-20173245;