NM_006282.5(STK4):c.442C>T (p.Arg148Ter) AND Combined immunodeficiency due to STK4 deficiency

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 3, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001389320.7

Allele description [Variation Report for NM_006282.5(STK4):c.442C>T (p.Arg148Ter)]

NM_006282.5(STK4):c.442C>T (p.Arg148Ter)

Gene:

STK4:serine/threonine kinase 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

20q13.12

Genomic location:

Preferred name:

NM_006282.5(STK4):c.442C>T (p.Arg148Ter)

HGVS:

NC_000020.11:g.44987213C>T
NG_032172.1:g.25735C>T
NM_001352385.2:c.442C>T
NM_006282.5:c.442C>TMANE SELECT
NP_001339314.1:p.Arg148Ter
NP_006273.1:p.Arg148Ter
LRG_535:g.25735C>T
NC_000020.10:g.43615854C>T

Protein change:

R148*

Links:

dbSNP: rs749441226

NCBI 1000 Genomes Browser:

rs749441226

Molecular consequence:

NM_001352385.2:c.442C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_006282.5:c.442C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Combined immunodeficiency due to STK4 deficiency (IMD110)
Synonyms:: STK4 DEFICIENCY; MST1 DEFICIENCY; T-cell immunodeficiency, recurrent infections, and autoimmunity with or without cardiac malformations
Identifiers:: MONDO: MONDO:0013934; MedGen: C3553943; Orphanet: 314689; OMIM: 614868

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001590642	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 12, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26801501, 22174160, 28492532
SCV002588771	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001590642

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 12, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002588771

DASA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 3, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Defective Leukocyte Adhesion and Chemotaxis Contributes to Combined Immunodeficiency in Humans with Autosomal Recessive MST1 Deficiency.

Dang TS, Willet JD, Griffin HR, Morgan NV, O'Boyle G, Arkwright PD, Hughes SM, Abinun M, Tee LJ, Barge D, Engelhardt KR, Jackson M, Cant AJ, Maher ER, Koref MS, Reynard LN, Ali S, Hambleton S.

J Clin Immunol. 2016 Feb;36(2):117-22. doi: 10.1007/s10875-016-0232-2. Epub 2016 Jan 22. Erratum in: J Clin Immunol. 2016 Apr;36(3):336-7.

PubMed [citation]

PMID:: 26801501
PMCID:: PMC4769310

MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival.

Nehme NT, Schmid JP, Debeurme F, André-Schmutz I, Lim A, Nitschke P, Rieux-Laucat F, Lutz P, Picard C, Mahlaoui N, Fischer A, de Saint Basile G.

Blood. 2012 Apr 12;119(15):3458-68. doi: 10.1182/blood-2011-09-378364. Epub 2011 Dec 14.

PubMed [citation]

PMID:: 22174160
PMCID:: PMC3824282

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001590642.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects STK4 protein function (PMID: 26801501). This variant has been observed in individual(s) with autosomal recessive combined immunodeficiency (PMID: 26801501). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs749441226, ExAC 0.02%). This sequence change creates a premature translational stop signal (p.Arg148*) in the STK4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in STK4 are known to be pathogenic (PMID: 22174160).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From DASA, SCV002588771.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

The c.442C>T;p.(Arg148*) variant creates a premature translational stop signal in the STK4 gene. It is expected to result in an absent or disrupted protein product - PVS1. ClinVar contains an entry for this variant (Clinvar ID: 1075656) - PS4_supporting. The variant is present at low allele frequencies population databases (rs749441226 – gnomAD 0.0001979%; ABraOM no frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Feb 14, 2024

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