rs147968

Variant names:

• chr16-85912233-T-C
• rs147968
• NM_002163.4:c.447+575T>C

Variant summary

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

The NM_002163.4(IRF8):​c.447+575T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.505 in 152,150 control chromosomes in the GnomAD database, including 20,486 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 0.51 (20486 hom., cov: 33)
• Consequence: IRF8 NM_002163.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.473
• Publications: 12 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 (AFR) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF8	NM_002163.4	c.447+575T>C		intron_variant	Intron 4 of 8	ENST00000268638.10	NP_002154.1
IRF8	NM_001363907.1	c.477+575T>C		intron_variant	Intron 4 of 8		NP_001350836.1
IRF8	NM_001363908.1	c.-60+575T>C		intron_variant	Intron 3 of 6		NP_001350837.1
IRF8	XM_047434052.1	c.477+575T>C		intron_variant	Intron 5 of 9		XP_047290008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF8	ENST00000268638.10	c.447+575T>C		intron_variant	Intron 4 of 8	1	NM_002163.4	ENSP00000268638.4

Frequencies

GnomAD3 genomes AF: 0.505 AC: 76747 AN: 152032 Hom.: 20423 Cov.: 33

Gnomad AFR AF: 0.677

Gnomad AMI AF: 0.521

Gnomad AMR AF: 0.433

Gnomad ASJ AF: 0.413

Gnomad EAS AF: 0.535

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.520

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

GnomAD4 genome AF: 0.505 AC: 76867 AN: 152150 Hom.: 20486 Cov.: 33 AF XY: 0.503 AC XY: 37407 AN XY: 74374

African (AFR) AF: 0.677 AC: 28118 AN: 41522

American (AMR) AF: 0.433 AC: 6616 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 1435 AN: 3472

East Asian (EAS) AF: 0.534 AC: 2763 AN: 5172

South Asian (SAS) AF: 0.362 AC: 1747 AN: 4828

European-Finnish (FIN) AF: 0.466 AC: 4921 AN: 10564

Middle Eastern (MID) AF: 0.527 AC: 154 AN: 292

European-Non Finnish (NFE) AF: 0.434 AC: 29525 AN: 67986

Other (OTH) AF: 0.526 AC: 1113 AN: 2114

Alfa AF: 0.475 Hom.: 13231

Bravo AF: 0.514

Asia WGS AF: 0.495 AC: 1718 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.010
DANN	Benign	0.55
PhyloP100		-0.47
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: rs147968; hg19: chr16-85945839;