rs17420378

Positions:

chr20-45000494-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006282.5(STK4):c.934G>A(p.Val312Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 1,613,508 control chromosomes in the GnomAD database, including 68,167 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.25 ( 5555 hom., cov: 32)

Exomes 𝑓: 0.28 ( 62612 hom. )

Consequence

STK4
NM_006282.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.77

Variant links:

Genes affected

STK4 (HGNC:11408): (serine/threonine kinase 4) The protein encoded by this gene is a cytoplasmic kinase that is structurally similar to the yeast Ste20p kinase, which acts upstream of the stress-induced mitogen-activated protein kinase cascade. The encoded protein can phosphorylate myelin basic protein and undergoes autophosphorylation. A caspase-cleaved fragment of the encoded protein has been shown to be capable of phosphorylating histone H2B. The particular phosphorylation catalyzed by this protein has been correlated with apoptosis, and it's possible that this protein induces the chromatin condensation observed in this process. [provided by RefSeq, Jul 2008]

STK4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019894838).

BP6

Variant 20-45000494-G-A is Benign according to our data. Variant chr20-45000494-G-A is described in ClinVar as [Benign]. Clinvar id is 1169470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK4	NM_006282.5 linkuse as main transcript	c.934G>A	p.Val312Met	missense_variant	8/11	ENST00000372806.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK4	ENST00000372806.8 linkuse as main transcript	c.934G>A	p.Val312Met	missense_variant	8/11	1	NM_006282.5	P1	Q13043-1

Frequencies

GnomAD3 genomes

AF:

0.252

AC:

38239

AN:

152034

Hom.:

5551

Cov.:

show subpopulations

Gnomad AFR

AF:

0.147

Gnomad AMI

AF:

0.388

Gnomad AMR

AF:

0.214

Gnomad ASJ

AF:

0.414

Gnomad EAS

AF:

0.0154

Gnomad SAS

AF:

0.259

Gnomad FIN

AF:

0.394

Gnomad MID

AF:

0.427

Gnomad NFE

AF:

0.307

Gnomad OTH

AF:

0.286

GnomAD3 exomes

AF:

0.263

AC:

65988

AN:

250956

Hom.:

10181

AF XY:

0.273

AC XY:

37058

AN XY:

135628

show subpopulations

Gnomad AFR exome

AF:

0.143

Gnomad AMR exome

AF:

0.146

Gnomad ASJ exome

AF:

0.413

Gnomad EAS exome

AF:

0.0115

Gnomad SAS exome

AF:

0.282

Gnomad FIN exome

AF:

0.397

Gnomad NFE exome

AF:

0.311

Gnomad OTH exome

AF:

0.296

GnomAD4 exome

AF:

0.284

AC:

415719

AN:

1461356

Hom.:

62612

Cov.:

AF XY:

0.287

AC XY:

208479

AN XY:

726974

show subpopulations

Gnomad4 AFR exome

AF:

0.142

Gnomad4 AMR exome

AF:

0.154

Gnomad4 ASJ exome

AF:

0.414

Gnomad4 EAS exome

AF:

0.0122

Gnomad4 SAS exome

AF:

0.282

Gnomad4 FIN exome

AF:

0.393

Gnomad4 NFE exome

AF:

0.295

Gnomad4 OTH exome

AF:

0.283

GnomAD4 genome

AF:

0.251

AC:

38258

AN:

152152

Hom.:

5555

Cov.:

AF XY:

0.255

AC XY:

18935

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.147

Gnomad4 AMR

AF:

0.214

Gnomad4 ASJ

AF:

0.414

Gnomad4 EAS

AF:

0.0154

Gnomad4 SAS

AF:

0.260

Gnomad4 FIN

AF:

0.394

Gnomad4 NFE

AF:

0.307

Gnomad4 OTH

AF:

0.283

Alfa

AF:

0.297

Hom.:

14995

Bravo

AF:

0.230

TwinsUK

AF:

0.295

AC:

1095

ALSPAC

AF:

0.297

AC:

1146

ESP6500AA

AF:

0.153

AC:

674

ESP6500EA

AF:

0.312

AC:

2684

ExAC

AF:

0.264

AC:

31999

Asia WGS

AF:

0.135

AC:

473

AN:

3478

EpiCase

AF:

0.316

EpiControl

AF:

0.312

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined immunodeficiency due to STK4 deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 43% of patients studied by a panel of primary immunodeficiencies. Number of patients: 41. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;.;.

Eigen

Benign

0.022

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.76

T;T;T

MetaRNN

Benign

0.0020

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;.;L

MutationTaster

Benign

0.16

P;P;P;P

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.12

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.12

T;T;T

Polyphen

0.0010

B;B;B

Vest4

0.080

MPC

0.31

ClinPred

0.0069

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.082

gMVP

0.30

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over