X-84106947-G-T

Variant names:

• chrX-84106947-G-T
• rs1194905372
• NM_014496.5:c.1205C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014496.5(RPS6KA6):​c.1205C>A​(p.Thr402Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000168 in 1,190,747 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T402I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 9.3e-7 (0 hom. 1 hem.)
• Consequence: RPS6KA6 NM_014496.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.05
• Publications: 0 publications found

Genes affected

RPS6KA6 (HGNC:10435): (ribosomal protein S6 kinase A6) This gene encodes a member of ribosomal S6 kinase family, serine-threonine protein kinases which are regulated by growth factors. The encoded protein may be distinct from other members of this family, however, as studies suggest it is not growth factor dependent and may not participate in the same signaling pathways. [provided by RefSeq, Jan 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18378925).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014496.5. 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
	RPS6KA6	NM_014496.5	MANE Select	c.1205C>A	p.Thr402Asn	missense	Exon 14 of 22	NP_055311.1	Q9UK32-1
	RPS6KA6	NM_001330512.1		c.1205C>A	p.Thr402Asn	missense	Exon 16 of 24	NP_001317441.1	Q9UK32-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA6	ENST00000262752.5	TSL:1 MANE Select	c.1205C>A	p.Thr402Asn	missense	Exon 14 of 22	ENSP00000262752.2	Q9UK32-1
	RPS6KA6	ENST00000620340.4	TSL:5	c.1205C>A	p.Thr402Asn	missense	Exon 14 of 22	ENSP00000483896.1	Q9UK32-2
	RPS6KA6	ENST00000911420.1		c.1205C>A	p.Thr402Asn	missense	Exon 14 of 22	ENSP00000581479.1

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111810 Hom.: 0 Cov.: 23

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: 0.0000189

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.27e-7 AC: 1 AN: 1078937 Hom.: 0 Cov.: 24 AF XY: 0.00000288 AC XY: 1 AN XY: 346791

African (AFR) AF: 0.00 AC: 0 AN: 25993

American (AMR) AF: 0.00 AC: 0 AN: 34386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19173

East Asian (EAS) AF: 0.00 AC: 0 AN: 29891

South Asian (SAS) AF: 0.00 AC: 0 AN: 52260

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40381

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4091

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 827366

Other (OTH) AF: 0.00 AC: 0 AN: 45396

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111810 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34004

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30841

American (AMR) AF: 0.00 AC: 0 AN: 10501

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3576

South Asian (SAS) AF: 0.00 AC: 0 AN: 2744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6061

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 53020

Other (OTH) AF: 0.00 AC: 0 AN: 1497

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.061	T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.34	N
PhyloP100		4.0
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.056
Sift	Benign	0.52	T
Sift4G	Benign	0.61	T
Polyphen		0.10	B
Vest4		0.068
MutPred		0.32		Gain of ubiquitination at K400 (P = 0.086)
MVP		0.51
MPC		0.59
ClinPred		0.31	T
GERP RS		4.9
Varity_R		0.10
gMVP		0.32
Mutation Taster		=82/18	polymorphism

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: rs1194905372; hg19: chrX-83361955;