chrX-84065098-T-C

Variant names:

• chrX-84065098-T-C
• rs149201069
• NM_014496.5:c.1985A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_014496.5(RPS6KA6):​c.1985A>G​(p.His662Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00068 in 1,186,477 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 261 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., 17 hem., cov: 22)
  • Exomes 𝑓: 0.00071 (0 hom. 244 hem.)
• Consequence: RPS6KA6 NM_014496.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.61
• Publications: 5 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.081795245).
• BS2: High Hemizygotes in GnomAd4 at 17 gene

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.1985A>G	p.His662Arg	missense	Exon 21 of 22	NP_055311.1	Q9UK32-1
	RPS6KA6	NM_001330512.1		c.1985A>G	p.His662Arg	missense	Exon 23 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.1985A>G	p.His662Arg	missense	Exon 21 of 22	ENSP00000262752.2	Q9UK32-1
	RPS6KA6	ENST00000620340.4	TSL:5	c.1985A>G	p.His662Arg	missense	Exon 21 of 22	ENSP00000483896.1	Q9UK32-2
	RPS6KA6	ENST00000911419.1		c.1478A>G	p.His493Arg	missense	Exon 15 of 16	ENSP00000581478.1

Frequencies

GnomAD3 genomes AF: 0.000389 AC: 43 AN: 110645 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00146

Gnomad AMR AF: 0.000193

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: 0.000699

Gnomad OTH AF: 0.00202

GnomAD2 exomes AF: 0.000325 AC: 57 AN: 175526 AF XY: 0.000377

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000787

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000632

Gnomad NFE exome AF: 0.000580

Gnomad OTH exome AF: 0.000468

GnomAD4 exome AF: 0.000710 AC: 764 AN: 1075832 Hom.: 0 Cov.: 26 AF XY: 0.000710 AC XY: 244 AN XY: 343420

African (AFR) AF: 0.00 AC: 0 AN: 25885

American (AMR) AF: 0.000236 AC: 8 AN: 33908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18897

East Asian (EAS) AF: 0.00 AC: 0 AN: 30011

South Asian (SAS) AF: 0.000374 AC: 19 AN: 50740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40141

Middle Eastern (MID) AF: 0.00273 AC: 11 AN: 4033

European-Non Finnish (NFE) AF: 0.000844 AC: 698 AN: 827009

Other (OTH) AF: 0.000619 AC: 28 AN: 45208

GnomAD4 genome AF: 0.000389 AC: 43 AN: 110645 Hom.: 0 Cov.: 22 AF XY: 0.000517 AC XY: 17 AN XY: 32863

African (AFR) AF: 0.00 AC: 0 AN: 30334

American (AMR) AF: 0.000193 AC: 2 AN: 10341

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3535

South Asian (SAS) AF: 0.00 AC: 0 AN: 2602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 233

European-Non Finnish (NFE) AF: 0.000699 AC: 37 AN: 52900

Other (OTH) AF: 0.00202 AC: 3 AN: 1485

Alfa AF: 0.000816 Hom.: 7

Bravo AF: 0.000434

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00119 AC: 8

ExAC AF: 0.000288 AC: 35

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.049	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.1	N
PhyloP100		5.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	1.2	N
REVEL	Uncertain	0.33
Sift	Benign	0.41	T
Sift4G	Benign	0.52	T
Polyphen		0.0010	B
Vest4		0.14
MVP		0.90
MPC		0.63
ClinPred		0.028	T
GERP RS		3.6
Varity_R		0.16
gMVP		0.68
Mutation Taster		=96/4	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: rs149201069; hg19: chrX-83320106; COSMIC: COSV53120643;