rs33963346

Variant names:

• chr20-45025072-C-T
• rs33963346
• NM_006282.5:c.1247C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 12/21 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.83
• Publications: 16 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 540526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK4	NM_006282.5	MANE Select	c.1247C>T	p.Pro416Leu	missense	Exon 10 of 11	NP_006273.1	Q13043-1
	STK4	NM_001352385.2		c.1247C>T	p.Pro416Leu	missense	Exon 10 of 12	NP_001339314.1	Q13043-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK4	ENST00000372806.8	TSL:1 MANE Select	c.1247C>T	p.Pro416Leu	missense	Exon 10 of 11	ENSP00000361892.3	Q13043-1
	STK4	ENST00000499879.8	TSL:1	c.1082C>T	p.Pro361Leu	missense	Exon 9 of 10	ENSP00000443514.1	F5H5B4
	STK4	ENST00000372801.5	TSL:2	c.1247C>T	p.Pro416Leu	missense	Exon 10 of 12	ENSP00000361887.1	Q13043-2

Frequencies

GnomAD3 genomes AF: 0.00710 AC: 1080 AN: 152168 Hom.: 6 Cov.: 32

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

GnomAD2 exomes AF: 0.00746 AC: 1865 AN: 250110 AF XY: 0.00793

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 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.: 30 AF XY: 0.0114 AC XY: 8306 AN XY: 726594

African (AFR) AF: 0.00191 AC: 64 AN: 33428

American (AMR) AF: 0.00462 AC: 206 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00609 AC: 159 AN: 26088

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39624

South Asian (SAS) AF: 0.00767 AC: 660 AN: 86036

European-Finnish (FIN) AF: 0.00302 AC: 161 AN: 53288

Middle Eastern (MID) AF: 0.00382 AC: 22 AN: 5762

European-Non Finnish (NFE) AF: 0.0135 AC: 14956 AN: 1111372

Other (OTH) AF: 0.00933 AC: 563 AN: 60336

GnomAD4 genome AF: 0.00708 AC: 1078 AN: 152286 Hom.: 6 Cov.: 32 AF XY: 0.00641 AC XY: 477 AN XY: 74462

African (AFR) AF: 0.00250 AC: 104 AN: 41548

American (AMR) AF: 0.00320 AC: 49 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4826

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10604

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0121 AC: 826 AN: 68024

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.0101 Hom.: 40

Bravo AF: 0.00680

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0128 AC: 110

ExAC AF: 0.00767 AC: 931

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Combined immunodeficiency due to STK4 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.67	N
PhyloP100		3.8
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.29
Sift	Benign	0.085	T
Sift4G	Uncertain	0.043	D
Polyphen		0.0	B
Vest4		0.22
MVP		0.84
MPC		0.31
ClinPred		0.020	T
GERP RS		6.2
Varity_R		0.064
gMVP		0.33
Mutation Taster		=97/3	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: rs33963346; hg19: chr20-43653713; COSMIC: COSV99064132;