NM_002163.4:c.-2+1339C>T

Variant names:

• chr16-85900562-C-T
• rs305084
• NM_002163.4:c.-2+1339C>T

Variant summary

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

The NM_002163.4(IRF8):​c.-2+1339C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.935 in 152,328 control chromosomes in the GnomAD database, including 66,718 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 0.94 (66718 hom., cov: 32)
• Consequence: IRF8 NM_002163.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.884
• Publications: 5 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 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.-2+1339C>T		intron	N/A	NP_002154.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF8	ENST00000268638.10	TSL:1 MANE Select	c.-2+1339C>T		intron	N/A	ENSP00000268638.4
	IRF8	ENST00000566369.2	TSL:3	c.-2+1339C>T		intron	N/A	ENSP00000455048.2
	IRF8	ENST00000565552.1	TSL:3	c.-320-366C>T		intron	N/A	ENSP00000455816.1

Frequencies

GnomAD3 genomes AF: 0.935 AC: 142322 AN: 152210 Hom.: 66658 Cov.: 32

Gnomad AFR AF: 0.981

Gnomad AMI AF: 0.964

Gnomad AMR AF: 0.919

Gnomad ASJ AF: 0.884

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.977

Gnomad FIN AF: 0.958

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.902

Gnomad OTH AF: 0.912

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

GnomAD4 genome AF: 0.935 AC: 142441 AN: 152328 Hom.: 66718 Cov.: 32 AF XY: 0.938 AC XY: 69897 AN XY: 74486

African (AFR) AF: 0.981 AC: 40800 AN: 41576

American (AMR) AF: 0.919 AC: 14061 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.884 AC: 3068 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5186 AN: 5186

South Asian (SAS) AF: 0.977 AC: 4716 AN: 4828

European-Finnish (FIN) AF: 0.958 AC: 10176 AN: 10622

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.902 AC: 61363 AN: 68022

Other (OTH) AF: 0.913 AC: 1932 AN: 2116

Alfa AF: 0.944 Hom.: 15712

Bravo AF: 0.934

Asia WGS AF: 0.989 AC: 3438 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.94
DANN	Benign	0.82
PhyloP100		-0.88
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: rs305084; hg19: chr16-85934168;