chr16-85903085-C-G
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_002163.4(IRF8):c.70C>G(p.Pro24Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
IRF8
NM_002163.4 missense
NM_002163.4 missense
Scores
1
9
9
Clinical Significance
Conservation
PhyloP100: 1.42
Genes affected
IRF8 (HGNC:5358): (interferon regulatory factor 8) Interferon consensus sequence-binding protein (ICSBP) is a transcription factor of the interferon (IFN) regulatory factor (IRF) family. Proteins of this family are composed of a conserved DNA-binding domain in the N-terminal region and a divergent C-terminal region that serves as the regulatory domain. The IRF family proteins bind to the IFN-stimulated response element (ISRE) and regulate expression of genes stimulated by type I IFNs, namely IFN-alpha and IFN-beta. IRF family proteins also control expression of IFN-alpha and IFN-beta-regulated genes that are induced by viral infection. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IRF8 | NM_002163.4 | c.70C>G | p.Pro24Ala | missense_variant | 2/9 | ENST00000268638.10 | |
IRF8 | NM_001363907.1 | c.100C>G | p.Pro34Ala | missense_variant | 2/9 | ||
IRF8 | XM_047434052.1 | c.100C>G | p.Pro34Ala | missense_variant | 3/10 | ||
IRF8 | NM_001363908.1 | c.-437C>G | 5_prime_UTR_variant | 1/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IRF8 | ENST00000268638.10 | c.70C>G | p.Pro24Ala | missense_variant | 2/9 | 1 | NM_002163.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461856Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727230
GnomAD4 exome
AF:
AC:
1
AN:
1461856
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
727230
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency;C4016741:Immunodeficiency 32B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 21, 2019 | Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with IRF8-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with alanine at codon 24 of the IRF8 protein (p.Pro24Ala). The proline residue is moderately conserved and there is a small physicochemical difference between proline and alanine. 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Pathogenic
D;.;D;.;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
M;.;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D
REVEL
Uncertain
Sift
Benign
T;T;T;T;T
Sift4G
Benign
T;T;T;T;T
Polyphen
B;.;.;.;.
Vest4
MutPred
Gain of catalytic residue at P24 (P = 0.0134);Gain of catalytic residue at P24 (P = 0.0134);Gain of catalytic residue at P24 (P = 0.0134);Gain of catalytic residue at P24 (P = 0.0134);Gain of catalytic residue at P24 (P = 0.0134);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at