rs148746145

Positions:

• chr16-85918497-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

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 (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: IRF8 NM_002163.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.35

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRF8	NM_002163.4	c.682C>T	p.Arg228Cys	missense_variant	7/9	ENST00000268638.10	NP_002154.1
IRF8	NM_001363907.1	c.712C>T	p.Arg238Cys	missense_variant	7/9		NP_001350836.1
IRF8	NM_001363908.1	c.70C>T	p.Arg24Cys	missense_variant	5/7		NP_001350837.1
IRF8	XM_047434052.1	c.712C>T	p.Arg238Cys	missense_variant	8/10		XP_047290008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRF8	ENST00000268638.10	c.682C>T	p.Arg228Cys	missense_variant	7/9	1	NM_002163.4	ENSP00000268638	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000858 AC: 2 AN: 233026 Hom.: 0 AF XY: 0.00000782 AC XY: 1 AN XY: 127924

Gnomad AFR exome AF: 0.0000669

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000929

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000833 AC: 12 AN: 1441104 Hom.: 0 Cov.: 31 AF XY: 0.0000112 AC XY: 8 AN XY: 716064

Gnomad4 AFR exome AF: 0.0000902

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000632

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ESP6500AA AF: 0.000230 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

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

Labcorp Genetics (formerly Invitae), Labcorp

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;D;D
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.8	M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.7	D;D;D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D
Polyphen		0.38	B;.;.;.
Vest4		0.51
MVP		0.92
MPC		0.75
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.52
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs148746145; hg19: chr16-85952103;