Genetic Variant STK4:c.35+624T>A (chr20-44967227-T-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_006282.5(STK4):c.35+624T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.081 in 985,110 control chromosomes in the GnomAD database, including 3,518 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.091 ( 755 hom., cov: 32)

Exomes 𝑓: 0.079 ( 2763 hom. )

Consequence

STK4
NM_006282.5 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.30

Publications

5 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, ClinGen, Orphanet, PanelApp Australia

STK4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant 20-44967227-T-A is Benign according to our data. Variant chr20-44967227-T-A is described in ClinVar as Benign. ClinVar VariationId is 2688246.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006282.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
STK4	NM_006282.5	MANE Select	c.35+624T>A	intron	N/A	NP_006273.1	Q13043-1
STK4	NM_001352385.2		c.35+624T>A	intron	N/A	NP_001339314.1	Q13043-2
STK4	NR_147974.2		n.92+624T>A	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
STK4	ENST00000372806.8	TSL:1 MANE Select	c.35+624T>A	intron	N/A	ENSP00000361892.3	Q13043-1
STK4	ENST00000499879.8	TSL:1	c.35+624T>A	intron	N/A	ENSP00000443514.1	F5H5B4
STK4	ENST00000488618.2	TSL:1	n.91+624T>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0907

AC:

13784

AN:

152048

Hom.:

754

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0607

Gnomad AMI

AF:

0.0833

Gnomad AMR

AF:

0.178

Gnomad ASJ

AF:

0.119

Gnomad EAS

AF:

0.187

Gnomad SAS

AF:

0.0608

Gnomad FIN

AF:

0.0957

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0809

Gnomad OTH

AF:

0.120

GnomAD4 exome

AF:

0.0793

AC:

66039

AN:

832944

Hom.:

2763

Cov.:

AF XY:

0.0793

AC XY:

30495

AN XY:

384644

show subpopulations

African (AFR)

AF:

0.0610

AC:

963

AN:

15780

American (AMR)

AF:

0.222

AC:

218

AN:

984

Ashkenazi Jewish (ASJ)

AF:

0.117

AC:

601

AN:

5150

East Asian (EAS)

AF:

0.194

AC:

705

AN:

3630

South Asian (SAS)

AF:

0.0633

AC:

1041

AN:

16458

European-Finnish (FIN)

AF:

0.0652

AC:

AN:

276

Middle Eastern (MID)

AF:

0.135

AC:

218

AN:

1620

European-Non Finnish (NFE)

AF:

0.0784

AC:

59719

AN:

761752

Other (OTH)

AF:

0.0936

AC:

2556

AN:

27294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

2862

5725

8587

11450

14312

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3036

6072

9108

12144

15180

<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:

0.0906

AC:

13791

AN:

152166

Hom.:

755

Cov.:

AF XY:

0.0946

AC XY:

7037

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0606

AC:

2517

AN:

41524

American (AMR)

AF:

0.178

AC:

2729

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

411

AN:

3466

East Asian (EAS)

AF:

0.188

AC:

972

AN:

5168

South Asian (SAS)

AF:

0.0615

AC:

296

AN:

4814

European-Finnish (FIN)

AF:

0.0957

AC:

1013

AN:

10586

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0808

AC:

5497

AN:

67994

Other (OTH)

AF:

0.118

AC:

249

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

615

1229

1844

2458

3073

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

154

308

462

616

770

<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:

0.0889

Hom.:

Bravo

AF:

0.0994

Asia WGS

AF:

0.114

AC:

396

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

8.8

(source)

DANN

Benign

0.91

PhyloP100

1.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.37

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.37

Position offset: 2

DS_DG_spliceai

0.20

Position offset: 44

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over