20-45000494-G-A

Variant names:

• chr20-45000494-G-A
• rs17420378
• NM_006282.5:c.934G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006282.5(STK4):​c.934G>A​(p.Val312Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 1,613,508 control chromosomes in the GnomAD database, including 68,167 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5555 hom., cov: 32)
  • Exomes 𝑓: 0.28 (62612 hom.)
• Consequence: STK4 NM_006282.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.77
• Publications: 31 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019894838).
• BP6: Variant 20-45000494-G-A is Benign according to our data. Variant chr20-45000494-G-A is described in ClinVar as Benign. ClinVar VariationId is 1169470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.304 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK4	NM_006282.5	MANE Select	c.934G>A	p.Val312Met	missense	Exon 8 of 11	NP_006273.1
	STK4	NM_001352385.2		c.934G>A	p.Val312Met	missense	Exon 8 of 12	NP_001339314.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK4	ENST00000372806.8	TSL:1 MANE Select	c.934G>A	p.Val312Met	missense	Exon 8 of 11	ENSP00000361892.3
	STK4	ENST00000499879.8	TSL:1	c.769G>A	p.Val257Met	missense	Exon 7 of 10	ENSP00000443514.1
	STK4	ENST00000372801.5	TSL:2	c.934G>A	p.Val312Met	missense	Exon 8 of 12	ENSP00000361887.1

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38239 AN: 152034 Hom.: 5551 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.0154

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.286

GnomAD2 exomes AF: 0.263 AC: 65988 AN: 250956 AF XY: 0.273

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.413

Gnomad EAS exome AF: 0.0115

Gnomad FIN exome AF: 0.397

Gnomad NFE exome AF: 0.311

Gnomad OTH exome AF: 0.296

GnomAD4 exome AF: 0.284 AC: 415719 AN: 1461356 Hom.: 62612 Cov.: 34 AF XY: 0.287 AC XY: 208479 AN XY: 726974

African (AFR) AF: 0.142 AC: 4738 AN: 33472

American (AMR) AF: 0.154 AC: 6879 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 10800 AN: 26112

East Asian (EAS) AF: 0.0122 AC: 483 AN: 39696

South Asian (SAS) AF: 0.282 AC: 24348 AN: 86212

European-Finnish (FIN) AF: 0.393 AC: 20985 AN: 53364

Middle Eastern (MID) AF: 0.348 AC: 2008 AN: 5766

European-Non Finnish (NFE) AF: 0.295 AC: 328418 AN: 1111668

Other (OTH) AF: 0.283 AC: 17060 AN: 60364

GnomAD4 genome AF: 0.251 AC: 38258 AN: 152152 Hom.: 5555 Cov.: 32 AF XY: 0.255 AC XY: 18935 AN XY: 74348

African (AFR) AF: 0.147 AC: 6110 AN: 41528

American (AMR) AF: 0.214 AC: 3276 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 1435 AN: 3470

East Asian (EAS) AF: 0.0154 AC: 80 AN: 5184

South Asian (SAS) AF: 0.260 AC: 1255 AN: 4822

European-Finnish (FIN) AF: 0.394 AC: 4147 AN: 10538

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.307 AC: 20877 AN: 67990

Other (OTH) AF: 0.283 AC: 597 AN: 2110

Alfa AF: 0.285 Hom.: 20006

Bravo AF: 0.230

TwinsUK AF: 0.295 AC: 1095

ALSPAC AF: 0.297 AC: 1146

ESP6500AA AF: 0.153 AC: 674

ESP6500EA AF: 0.312 AC: 2684

ExAC AF: 0.264 AC: 31999

Asia WGS AF: 0.135 AC: 473 AN: 3478

EpiCase AF: 0.316

EpiControl AF: 0.312

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined immunodeficiency due to STK4 deficiency Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 43% of patients studied by a panel of primary immunodeficiencies. Number of patients: 41. Only high quality variants are reported.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.022
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.8
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.12
Sift	Benign	0.13	T
Sift4G	Benign	0.12	T
Polyphen		0.0010	B
Vest4		0.080
MPC		0.31
ClinPred		0.0069	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.082
gMVP		0.30
Mutation Taster		=96/4	polymorphism (auto)

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: rs17420378; hg19: chr20-43629135; COSMIC: COSV65670082; COSMIC: COSV65670082;