rs148746145
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_002163.4(IRF8):c.682C>T(p.Arg228Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000833 in 1,441,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R228S) has been classified as Uncertain significance.
Frequency
Consequence
NM_002163.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IRF8 | NM_002163.4 | c.682C>T | p.Arg228Cys | missense_variant | 7/9 | ENST00000268638.10 | |
IRF8 | NM_001363907.1 | c.712C>T | p.Arg238Cys | missense_variant | 7/9 | ||
IRF8 | NM_001363908.1 | c.70C>T | p.Arg24Cys | missense_variant | 5/7 | ||
IRF8 | XM_047434052.1 | c.712C>T | p.Arg238Cys | missense_variant | 8/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IRF8 | ENST00000268638.10 | c.682C>T | p.Arg228Cys | missense_variant | 7/9 | 1 | NM_002163.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000858 AC: 2AN: 233026Hom.: 0 AF XY: 0.00000782 AC XY: 1AN XY: 127924
GnomAD4 exome AF: 0.00000833 AC: 12AN: 1441104Hom.: 0 Cov.: 31 AF XY: 0.0000112 AC XY: 8AN XY: 716064
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Immunodeficiency 32B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 04, 2020 | - - |
Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency;C4016741:Immunodeficiency 32B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2018 | This sequence change replaces arginine with cysteine at codon 228 of the IRF8 protein (p.Arg228Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with IRF8-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65". The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at