rs33963346

Positions:

chr20-45025072-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006282.5(STK4):c.1247C>T(p.Pro416Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0111 in 1,612,832 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0071 ( 6 hom., cov: 32)

Exomes 𝑓: 0.011 ( 114 hom. )

Consequence

STK4
NM_006282.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.83

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:

STK4 (HGNC:):

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=0.0074424148).

BP6

Variant 20-45025072-C-T is Benign according to our data. Variant chr20-45025072-C-T is described in ClinVar as [Benign]. Clinvar id is 540526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-45025072-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00708 (1078/152286) while in subpopulation NFE AF= 0.0121 (826/68024). AF 95% confidence interval is 0.0115. There are 6 homozygotes in gnomad4. There are 477 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK4	NM_006282.5 linkuse as main transcript	c.1247C>T	p.Pro416Leu	missense_variant	10/11	ENST00000372806.8	NP_006273.1	Q13043-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK4	ENST00000372806.8 linkuse as main transcript	c.1247C>T	p.Pro416Leu	missense_variant	10/11	1	NM_006282.5	ENSP00000361892.3		Q13043-1

Frequencies

GnomAD3 genomes

AF:

0.00710

AC:

1080

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00251

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00691

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00704

Gnomad FIN

AF:

0.00245

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0122

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00746

AC:

1865

AN:

250110

Hom.:

AF XY:

0.00793

AC XY:

1072

AN XY:

135216

show subpopulations

Gnomad AFR exome

AF:

0.00216

Gnomad AMR exome

AF:

0.00424

Gnomad ASJ exome

AF:

0.00617

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00706

Gnomad FIN exome

AF:

0.00302

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.00922

GnomAD4 exome

AF:

0.0115

AC:

16792

AN:

1460546

Hom.:

114

Cov.:

AF XY:

0.0114

AC XY:

8306

AN XY:

726594

show subpopulations

Gnomad4 AFR exome

AF:

0.00191

Gnomad4 AMR exome

AF:

0.00462

Gnomad4 ASJ exome

AF:

0.00609

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00767

Gnomad4 FIN exome

AF:

0.00302

Gnomad4 NFE exome

AF:

0.0135

Gnomad4 OTH exome

AF:

0.00933

GnomAD4 genome

AF:

0.00708

AC:

1078

AN:

152286

Hom.:

Cov.:

AF XY:

0.00641

AC XY:

477

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00250

Gnomad4 AMR

AF:

0.00320

Gnomad4 ASJ

AF:

0.00691

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00684

Gnomad4 FIN

AF:

0.00245

Gnomad4 NFE

AF:

0.0121

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.0105

Hom.:

Bravo

AF:

0.00680

TwinsUK

AF:

0.0135

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0128

AC:

110

ExAC

AF:

0.00767

AC:

931

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	STK4: BP4, BS1, BS2 -

Combined immunodeficiency due to STK4 deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;.;.

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

D;D;D

MetaRNN

Benign

0.0074

T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.67

N;.;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.9

N;N;N

REVEL

Uncertain

0.29

Sift

Benign

0.085

T;T;D

Sift4G

Uncertain

0.043

D;T;T

Polyphen

0.0

B;B;B

Vest4

0.22

MVP

0.84

MPC

0.31

ClinPred

0.020

GERP RS

6.2

Varity_R

0.064

gMVP

0.33

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