rs11545564

chr16-85909115-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002163.4(IRF8):c.300A>G(p.Gln100=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00609 in 1,614,148 control chromosomes in the GnomAD database, including 838 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (120 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (718 hom.)
• Consequence: IRF8 NM_002163.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.86

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 16-85909115-A-G is Benign according to our data. Variant chr16-85909115-A-G is described in ClinVar as [Benign]. Clinvar id is 475389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.097 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF8	NM_002163.4	c.300A>G	p.Gln100=	synonymous_variant	3/9	ENST00000268638.10
IRF8	NM_001363907.1	c.330A>G	p.Gln110=	synonymous_variant	3/9
IRF8	XM_047434052.1	c.330A>G	p.Gln110=	synonymous_variant	4/10
IRF8	NM_001363908.1	c.-207A>G		5_prime_UTR_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF8	ENST00000268638.10	c.300A>G	p.Gln100=	synonymous_variant	3/9	1	NM_002163.4	P1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1689 AN: 152176 Hom.: 116 Cov.: 33

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00501

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.0253 AC: 6374 AN: 251452 Hom.: 615 AF XY: 0.0187 AC XY: 2536 AN XY: 135908

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00555

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.0153

GnomAD4 exome AF: 0.00555 AC: 8120 AN: 1461854 Hom.: 718 Cov.: 31 AF XY: 0.00456 AC XY: 3315 AN XY: 727222

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.163

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00710

Gnomad4 SAS exome AF: 0.000649

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000197

Gnomad4 OTH exome AF: 0.00404

GnomAD4 genome AF: 0.0112 AC: 1705 AN: 152294 Hom.: 120 Cov.: 33 AF XY: 0.0129 AC XY: 962 AN XY: 74486

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00502

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00844 Hom.: 59

Bravo AF: 0.0203

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency;C4016741:Immunodeficiency 32B Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

IRF8-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	13
Dann	Benign	0.82

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: rs11545564; hg19: chr16-85942721;