NM_016123.4(IRAK4):c.784T>C (p.Tyr262His) AND Immunodeficiency 67

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 22, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001368247.7

Allele description [Variation Report for NM_016123.4(IRAK4):c.784T>C (p.Tyr262His)]

NM_016123.4(IRAK4):c.784T>C (p.Tyr262His)

Gene:

IRAK4:interleukin 1 receptor associated kinase 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q12

Genomic location:

Preferred name:

NM_016123.4(IRAK4):c.784T>C (p.Tyr262His)

HGVS:

NC_000012.12:g.43777697T>C
NG_009892.1:g.23754T>C
NM_001114182.3:c.784T>C
NM_001145256.2:c.412T>C
NM_001145257.2:c.412T>C
NM_001145258.2:c.412T>C
NM_001351338.2:c.412T>C
NM_001351339.2:c.412T>C
NM_001351340.2:c.412T>C
NM_001351341.2:c.412T>C
NM_001351342.2:c.412T>C
NM_001351343.2:c.175T>C
NM_001351344.2:c.175T>C
NM_001351345.2:c.784T>C
NM_016123.4:c.784T>CMANE SELECT
NP_001107654.1:p.Tyr262His
NP_001138728.1:p.Tyr138His
NP_001138729.1:p.Tyr138His
NP_001138730.1:p.Tyr138His
NP_001338267.1:p.Tyr138His
NP_001338268.1:p.Tyr138His
NP_001338269.1:p.Tyr138His
NP_001338270.1:p.Tyr138His
NP_001338271.1:p.Tyr138His
NP_001338272.1:p.Tyr59His
NP_001338273.1:p.Tyr59His
NP_001338274.1:p.Tyr262His
NP_057207.2:p.Tyr262His
LRG_75:g.23754T>C
NC_000012.11:g.44171500T>C

Protein change:

Y138H

Links:

dbSNP: rs2137999821

NCBI 1000 Genomes Browser:

rs2137999821

Molecular consequence:

NM_001114182.3:c.784T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001145256.2:c.412T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001145257.2:c.412T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001145258.2:c.412T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001351338.2:c.412T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001351339.2:c.412T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001351340.2:c.412T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001351341.2:c.412T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001351342.2:c.412T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001351343.2:c.175T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001351344.2:c.175T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001351345.2:c.784T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_016123.4:c.784T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Immunodeficiency 67
Synonyms:: IRAK4 deficiency; Interleukin receptor-associated kinase deficiency; Immunodeficiency due to interleukin-1 receptor-associated kinase-4 deficiency
Identifiers:: MONDO: MONDO:0011888; MedGen: C1843256; Orphanet: 70592; OMIM: 607676

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001564633	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 22, 2021)	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

SCV001564633

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 22, 2021)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001564633.4

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

Description

This variant has not been reported in the literature in individuals with IRAK4-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with histidine at codon 262 of the IRAK4 protein (p.Tyr262His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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

Last Updated: Sep 29, 2024

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