rs11545564

Variant names:

• chr16-85909115-A-G
• rs11545564
• NM_002163.4:c.300A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002163.4(IRF8):​c.300A>G​(p.Gln100Gln) 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:3
• Conservation: PhyloP100: 3.86
• Publications: 2 publications found

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]

IRF8 Gene-Disease associations (from GenCC):

• Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Illumina
• immunodeficiency 32B

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002163.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF8	NM_002163.4	MANE Select	c.300A>G	p.Gln100Gln	synonymous	Exon 3 of 9	NP_002154.1	Q02556
	IRF8	NM_001363907.1		c.330A>G	p.Gln110Gln	synonymous	Exon 3 of 9	NP_001350836.1
	IRF8	NM_001363908.1		c.-207A>G		5_prime_UTR	Exon 2 of 7	NP_001350837.1	H3BRT4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF8	ENST00000268638.10	TSL:1 MANE Select	c.300A>G	p.Gln100Gln	synonymous	Exon 3 of 9	ENSP00000268638.4	Q02556
	IRF8	ENST00000563180.1	TSL:1	c.300A>G	p.Gln100Gln	synonymous	Exon 2 of 2	ENSP00000458047.1	H3BVC2
	IRF8	ENST00000564803.6	TSL:2	c.300A>G	p.Gln100Gln	synonymous	Exon 3 of 9	ENSP00000456992.2	Q02556

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

GnomAD2 exomes AF: 0.0253 AC: 6374 AN: 251452 AF XY: 0.0187

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 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

African (AFR) AF: 0.00102 AC: 34 AN: 33480

American (AMR) AF: 0.163 AC: 7282 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00710 AC: 282 AN: 39698

South Asian (SAS) AF: 0.000649 AC: 56 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53394

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000197 AC: 219 AN: 1112002

Other (OTH) AF: 0.00404 AC: 244 AN: 60396

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

African (AFR) AF: 0.00173 AC: 72 AN: 41566

American (AMR) AF: 0.101 AC: 1547 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00502 AC: 26 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68020

Other (OTH) AF: 0.0142 AC: 30 AN: 2114

Alfa AF: 0.00667 Hom.: 63

Bravo AF: 0.0203

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	IRF8-related disorder (1)
-	-	1	Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency;C4751209:Immunodeficiency 32B (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	13
DANN	Benign	0.82
PhyloP100		3.9
PromoterAI		0.093	Neutral
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11545564; hg19: chr16-85942721;