16-85920201-C-G

Position:

• chr16-85920201-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002163.4(IRF8):​c.1081C>G​(p.Arg361Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000714 in 1,400,424 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: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: IRF8 NM_002163.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.45

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRF8	NM_002163.4	c.1081C>G	p.Arg361Gly	missense_variant	8/9	ENST00000268638.10	NP_002154.1
IRF8	NM_001363907.1	c.1111C>G	p.Arg371Gly	missense_variant	8/9		NP_001350836.1
IRF8	NM_001363908.1	c.469C>G	p.Arg157Gly	missense_variant	6/7		NP_001350837.1
IRF8	XM_047434052.1	c.1111C>G	p.Arg371Gly	missense_variant	9/10		XP_047290008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRF8	ENST00000268638.10	c.1081C>G	p.Arg361Gly	missense_variant	8/9	1	NM_002163.4	ENSP00000268638	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251238 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135812

Gnomad AFR exome AF: 0.0000616

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1400424 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 698896

Gnomad4 AFR exome AF: 0.0000311

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

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

Labcorp Genetics (formerly Invitae), Labcorp

Jun 11, 2023

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. 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 not expected to disrupt IRF8 protein function. ClinVar contains an entry for this variant (Variation ID: 1690788). This variant has not been reported in the literature in individuals affected with IRF8-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 361 of the IRF8 protein (p.Arg361Gly). -

See cases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Feb 06, 2020

ACMG classification criteria: PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;D;D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.6	M;.;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0030	D;D;D
Sift4G	Benign	0.081	T;T;T
Polyphen		0.95	P;.;.
Vest4		0.63
MutPred		0.55		Loss of solvent accessibility (P = 0.0509);.;.;
MVP		0.83
MPC		1.7
ClinPred		0.93	D
GERP RS		5.2
Varity_R		0.34
gMVP		0.33

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: rs771773479; hg19: chr16-85953807;