chr20-45001270-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006282.5(STK4):c.1064T>C(p.Ile355Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00164 in 1,614,118 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 12 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 53 hom. )

Consequence

STK4
NM_006282.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 5.75

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

combined immunodeficiency due to STK4 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen

STK4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031707287).

BP6

Variant 20-45001270-T-C is Benign according to our data. Variant chr20-45001270-T-C is described in ClinVar as Benign. ClinVar VariationId is 540524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.002 (304/152256) while in subpopulation EAS AF = 0.0551 (286/5188). AF 95% confidence interval is 0.0499. There are 12 homozygotes in GnomAd4. There are 186 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK4	NM_006282.5 link	c.1064T>C	p.Ile355Thr	missense_variant	Exon 9 of 11	ENST00000372806.8	NP_006273.1	Q13043-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK4	ENST00000372806.8 link	c.1064T>C	p.Ile355Thr	missense_variant	Exon 9 of 11	1	NM_006282.5	ENSP00000361892.3		Q13043-1

Frequencies

GnomAD3 genomes

AF:

0.00200

AC:

305

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0552

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00496

AC:

1247

AN:

251322

AF XY:

0.00484

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0633

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000979

GnomAD4 exome

AF:

0.00160

AC:

2341

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

1189

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0484

AC:

1920

AN:

39692

South Asian (SAS)

AF:

0.00279

AC:

241

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000450

AC:

AN:

1111996

Other (OTH)

AF:

0.00207

AC:

125

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

122

243

365

486

608

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00200

AC:

304

AN:

152256

Hom.:

Cov.:

AF XY:

0.00250

AC XY:

186

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41562

American (AMR)

AF:

0.000196

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.0551

AC:

286

AN:

5188

South Asian (SAS)

AF:

0.00249

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68014

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00235

Hom.:

Bravo

AF:

0.00289

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00451

AC:

547

Asia WGS

AF:

0.0150

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Combined immunodeficiency due to STK4 deficiency

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;.;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;T;T

MetaRNN

Benign

0.0032

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;.;L

PhyloP100

5.8

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.1

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.062

T;D;D

Sift4G

Benign

0.26

T;T;T

Polyphen

0.17

B;B;B

Vest4

0.40

MVP

0.55

MPC

0.40

ClinPred

0.025

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.33

gMVP

0.38

Mutation Taster

=89/11

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over