16-85917748-A-G

Variant names:

• chr16-85917748-A-G
• rs8054065
• NM_002163.4:c.602-669A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002163.4(IRF8):​c.602-669A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.503 in 151,992 control chromosomes in the GnomAD database, including 19,652 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (19652 hom., cov: 32)
• Consequence: IRF8 NM_002163.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.969
• Publications: 11 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF8	NM_002163.4	c.602-669A>G		intron_variant	Intron 6 of 8	ENST00000268638.10	NP_002154.1
IRF8	NM_001363907.1	c.632-669A>G		intron_variant	Intron 6 of 8		NP_001350836.1
IRF8	NM_001363908.1	c.-11-669A>G		intron_variant	Intron 4 of 6		NP_001350837.1
IRF8	XM_047434052.1	c.632-669A>G		intron_variant	Intron 7 of 9		XP_047290008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF8	ENST00000268638.10	c.602-669A>G		intron_variant	Intron 6 of 8	1	NM_002163.4	ENSP00000268638.4

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76440 AN: 151876 Hom.: 19628 Cov.: 32

Gnomad AFR AF: 0.562

Gnomad AMI AF: 0.602

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.491

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.530

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.516

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.503 AC: 76506 AN: 151992 Hom.: 19652 Cov.: 32 AF XY: 0.498 AC XY: 37021 AN XY: 74284

African (AFR) AF: 0.561 AC: 23256 AN: 41422

American (AMR) AF: 0.410 AC: 6267 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 1639 AN: 3468

East Asian (EAS) AF: 0.491 AC: 2538 AN: 5172

South Asian (SAS) AF: 0.339 AC: 1631 AN: 4818

European-Finnish (FIN) AF: 0.530 AC: 5601 AN: 10564

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.497 AC: 33763 AN: 67964

Other (OTH) AF: 0.523 AC: 1102 AN: 2108

Alfa AF: 0.514 Hom.: 5714

Bravo AF: 0.503

Asia WGS AF: 0.453 AC: 1575 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.9
DANN	Benign	0.53
PhyloP100		-0.97
Mutation Taster		=100/0	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: rs8054065; hg19: chr16-85951354;