X-84106963-C-T

Variant names:

• chrX-84106963-C-T
• NM_014496.5:c.1189G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014496.5(RPS6KA6):​c.1189G>A​(p.Glu397Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000277 in 1,081,786 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000028 (0 hom. 0 hem.)
• Consequence: RPS6KA6 NM_014496.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.47

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38654763).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KA6	NM_014496.5	c.1189G>A	p.Glu397Lys	missense_variant	Exon 14 of 22	ENST00000262752.5	NP_055311.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS6KA6	ENST00000262752.5	c.1189G>A	p.Glu397Lys	missense_variant	Exon 14 of 22	1	NM_014496.5	ENSP00000262752.2
RPS6KA6	ENST00000620340.4	c.1189G>A	p.Glu397Lys	missense_variant	Exon 14 of 22	5		ENSP00000483896.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000277 AC: 3 AN: 1081786 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 349200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000362

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 08, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1189G>A (p.E397K) alteration is located in exon 14 (coding exon 14) of the RPS6KA6 gene. This alteration results from a G to A substitution at nucleotide position 1189, causing the glutamic acid (E) at amino acid position 397 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	.;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.9	.;N
REVEL	Benign	0.24
Sift	Benign	0.32	.;T
Sift4G	Benign	0.51	T;T
Polyphen		0.13	.;B
Vest4		0.13
MutPred		0.50		Gain of ubiquitination at E397 (P = 0.0238);Gain of ubiquitination at E397 (P = 0.0238);
MVP		0.75
MPC		0.59
ClinPred		0.90	D
GERP RS		4.9
Varity_R		0.57
gMVP		0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-83361971;