rs141209982
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_016123.4(IRAK4):āc.529A>Gā(p.Thr177Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000537 in 1,610,808 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00041 ( 0 hom., cov: 32)
Exomes š: 0.00055 ( 1 hom. )
Consequence
IRAK4
NM_016123.4 missense
NM_016123.4 missense
Scores
12
3
1
Clinical Significance
Conservation
PhyloP100: 8.17
Genes affected
IRAK4 (HGNC:17967): (interleukin 1 receptor associated kinase 4) This gene encodes a kinase that activates NF-kappaB in both the Toll-like receptor (TLR) and T-cell receptor (TCR) signaling pathways. The protein is essential for most innate immune responses. Mutations in this gene result in IRAK4 deficiency and recurrent invasive pneumococcal disease. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.897
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IRAK4 | NM_016123.4 | c.529A>G | p.Thr177Ala | missense_variant | 5/12 | ENST00000613694.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IRAK4 | ENST00000613694.5 | c.529A>G | p.Thr177Ala | missense_variant | 5/12 | 1 | NM_016123.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000414 AC: 63AN: 152152Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000347 AC: 87AN: 251044Hom.: 0 AF XY: 0.000346 AC XY: 47AN XY: 135698
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GnomAD4 exome AF: 0.000550 AC: 802AN: 1458538Hom.: 1 Cov.: 30 AF XY: 0.000551 AC XY: 400AN XY: 725442
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GnomAD4 genome ? AF: 0.000414 AC: 63AN: 152270Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19AN XY: 74458
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Immunodeficiency 67 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 24, 2022 | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 177 of the IRAK4 protein (p.Thr177Ala). This variant is present in population databases (rs141209982, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with IRAK4-related conditions. ClinVar contains an entry for this variant (Variation ID: 574442). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IRAK4 protein function. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 15, 2024 | The c.529A>G (p.T177A) alteration is located in exon 5 (coding exon 4) of the IRAK4 gene. This alteration results from a A to G substitution at nucleotide position 529, causing the threonine (T) at amino acid position 177 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;.;D;D
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
0.97
.;.;D;D;.
Vest4
MVP
MPC
0.091
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at