NM_004586.3:c.1000-7C>T

Variant names:

• chrX-20176359-G-A
• rs1555933444
• NM_004586.3:c.1000-7C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_004586.3(RPS6KA3):​c.1000-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: RPS6KA3 NM_004586.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001906
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0750
• 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, ClinGen, G2P
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-20176359-G-A is Benign according to our data. Variant chrX-20176359-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 459261.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA3	NM_004586.3	MANE Select	c.1000-7C>T		splice_region intron	N/A	NP_004577.1
	RPS6KA3	NM_001438340.1		c.916-7C>T		splice_region intron	N/A	NP_001425269.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA3	ENST00000379565.9	TSL:1 MANE Select	c.1000-7C>T		splice_region intron	N/A	ENSP00000368884.3
	RPS6KA3	ENST00000642835.1		c.916-7C>T		splice_region intron	N/A	ENSP00000494769.1
	RPS6KA3	ENST00000643085.1		c.916-7C>T		splice_region intron	N/A	ENSP00000496271.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 107902 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1036070 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 312138

African (AFR) AF: 0.00 AC: 0 AN: 25037

American (AMR) AF: 0.00 AC: 0 AN: 34458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18919

East Asian (EAS) AF: 0.00 AC: 0 AN: 29931

South Asian (SAS) AF: 0.00 AC: 0 AN: 51941

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3962

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 787460

Other (OTH) AF: 0.00 AC: 0 AN: 43908

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 107902 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 30916

African (AFR) AF: 0.00 AC: 0 AN: 29546

American (AMR) AF: 0.00 AC: 0 AN: 10029

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2612

East Asian (EAS) AF: 0.00 AC: 0 AN: 3492

South Asian (SAS) AF: 0.00 AC: 0 AN: 2541

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5084

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 232

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52229

Other (OTH) AF: 0.00 AC: 0 AN: 1460

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Coffin-Lowry syndrome;C0796225:Intellectual disability, X-linked 19 Benign:1

Jul 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.78
DANN	Benign	0.53
PhyloP100		-0.075

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0080
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: rs1555933444; hg19: chrX-20194477;