16-85917315-A-G

Variant names:

• chr16-85917315-A-G
• rs4843860
• NM_002163.4:c.602-1102A>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.602-1102A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 152,118 control chromosomes in the GnomAD database, including 4,200 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 0.22 (4200 hom., cov: 32)
• Consequence: IRF8 NM_002163.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.30
• Publications: 16 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.3 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF8	NM_002163.4	MANE Select	c.602-1102A>G		intron	N/A	NP_002154.1
	IRF8	NM_001363907.1		c.632-1102A>G		intron	N/A	NP_001350836.1
	IRF8	NM_001363908.1		c.-11-1102A>G		intron	N/A	NP_001350837.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF8	ENST00000268638.10	TSL:1 MANE Select	c.602-1102A>G		intron	N/A	ENSP00000268638.4
	IRF8	ENST00000564803.6	TSL:2	c.602-1102A>G		intron	N/A	ENSP00000456992.2
	IRF8	ENST00000696887.1		c.602-1102A>G		intron	N/A	ENSP00000512953.1

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34201 AN: 152000 Hom.: 4198 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.408

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.290

Gnomad EAS AF: 0.313

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.268

Gnomad OTH AF: 0.265

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

GnomAD4 genome AF: 0.225 AC: 34212 AN: 152118 Hom.: 4200 Cov.: 32 AF XY: 0.223 AC XY: 16592 AN XY: 74370

African (AFR) AF: 0.135 AC: 5620 AN: 41530

American (AMR) AF: 0.212 AC: 3228 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 1004 AN: 3466

East Asian (EAS) AF: 0.312 AC: 1618 AN: 5180

South Asian (SAS) AF: 0.213 AC: 1026 AN: 4818

European-Finnish (FIN) AF: 0.231 AC: 2447 AN: 10578

Middle Eastern (MID) AF: 0.384 AC: 112 AN: 292

European-Non Finnish (NFE) AF: 0.268 AC: 18221 AN: 67968

Other (OTH) AF: 0.267 AC: 564 AN: 2112

Alfa AF: 0.253 Hom.: 20190

Bravo AF: 0.223

Asia WGS AF: 0.267 AC: 928 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.1
DANN	Benign	0.74
PhyloP100		-3.3
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: rs4843860; hg19: chr16-85950921;