20-44995083-A-G

Variant names:

• chr20-44995083-A-G
• rs528301360
• NM_006282.5:c.526-7A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_006282.5(STK4):​c.526-7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,572,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: STK4 NM_006282.5 splice_region, intron
• Scores: Splicing: ADA: 0.00004434
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.74
• Publications: 0 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, Orphanet, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 20-44995083-A-G is Benign according to our data. Variant chr20-44995083-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 473299.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK4	NM_006282.5	MANE Select	c.526-7A>G		splice_region intron	N/A	NP_006273.1
	STK4	NM_001352385.2		c.526-7A>G		splice_region intron	N/A	NP_001339314.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK4	ENST00000372806.8	TSL:1 MANE Select	c.526-7A>G		splice_region intron	N/A	ENSP00000361892.3
	STK4	ENST00000499879.8	TSL:1	c.361-7A>G		splice_region intron	N/A	ENSP00000443514.1
	STK4	ENST00000372801.5	TSL:2	c.526-7A>G		splice_region intron	N/A	ENSP00000361887.1

Frequencies

GnomAD3 genomes AF: 0.000264 AC: 38 AN: 143850 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000425

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000563

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000348

Gnomad OTH AF: 0.000520

GnomAD2 exomes AF: 0.000280 AC: 66 AN: 235660 AF XY: 0.000266

Gnomad AFR exome AF: 0.0000671

Gnomad AMR exome AF: 0.000384

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000655

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.000179

GnomAD4 exome AF: 0.000228 AC: 326 AN: 1429020 Hom.: 0 Cov.: 31 AF XY: 0.000235 AC XY: 167 AN XY: 710482

African (AFR) AF: 0.0000622 AC: 2 AN: 32168

American (AMR) AF: 0.000331 AC: 14 AN: 42248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25236

East Asian (EAS) AF: 0.00 AC: 0 AN: 37710

South Asian (SAS) AF: 0.00 AC: 0 AN: 80700

European-Finnish (FIN) AF: 0.000535 AC: 28 AN: 52334

Middle Eastern (MID) AF: 0.000530 AC: 3 AN: 5660

European-Non Finnish (NFE) AF: 0.000250 AC: 274 AN: 1094142

Other (OTH) AF: 0.0000850 AC: 5 AN: 58822

GnomAD4 genome AF: 0.000264 AC: 38 AN: 143850 Hom.: 0 Cov.: 29 AF XY: 0.000259 AC XY: 18 AN XY: 69408

African (AFR) AF: 0.0000775 AC: 3 AN: 38694

American (AMR) AF: 0.000425 AC: 6 AN: 14108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3396

East Asian (EAS) AF: 0.00 AC: 0 AN: 4936

South Asian (SAS) AF: 0.00 AC: 0 AN: 4632

European-Finnish (FIN) AF: 0.000563 AC: 5 AN: 8888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.000348 AC: 23 AN: 66072

Other (OTH) AF: 0.000520 AC: 1 AN: 1924

Alfa AF: 0.000204 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Combined immunodeficiency due to STK4 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.19
DANN	Benign	0.56
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000044
dbscSNV1_RF	Benign	0.0020
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: rs528301360; hg19: chr20-43623724;