16-85911217-T-G

Variant names:

• chr16-85911217-T-G
• rs2292982
• NM_002163.4:c.359-353T>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.359-353T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.41 in 152,148 control chromosomes in the GnomAD database, including 13,741 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 0.41 (13741 hom., cov: 34)
• Consequence: IRF8 NM_002163.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0110
• Publications: 22 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF8	NM_002163.4	c.359-353T>G		intron_variant	Intron 3 of 8	ENST00000268638.10	NP_002154.1
IRF8	NM_001363907.1	c.389-353T>G		intron_variant	Intron 3 of 8		NP_001350836.1
IRF8	NM_001363908.1	c.-148-353T>G		intron_variant	Intron 2 of 6		NP_001350837.1
IRF8	XM_047434052.1	c.389-353T>G		intron_variant	Intron 4 of 9		XP_047290008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF8	ENST00000268638.10	c.359-353T>G		intron_variant	Intron 3 of 8	1	NM_002163.4	ENSP00000268638.4

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62322 AN: 152030 Hom.: 13689 Cov.: 34

Gnomad AFR AF: 0.581

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.349

Gnomad ASJ AF: 0.333

Gnomad EAS AF: 0.340

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.343

Gnomad OTH AF: 0.414

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

GnomAD4 genome AF: 0.410 AC: 62428 AN: 152148 Hom.: 13741 Cov.: 34 AF XY: 0.409 AC XY: 30451 AN XY: 74384

African (AFR) AF: 0.581 AC: 24106 AN: 41468

American (AMR) AF: 0.349 AC: 5335 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 1157 AN: 3470

East Asian (EAS) AF: 0.339 AC: 1759 AN: 5184

South Asian (SAS) AF: 0.267 AC: 1289 AN: 4824

European-Finnish (FIN) AF: 0.400 AC: 4241 AN: 10598

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.342 AC: 23287 AN: 67992

Other (OTH) AF: 0.420 AC: 887 AN: 2114

Alfa AF: 0.362 Hom.: 28153

Bravo AF: 0.418

Asia WGS AF: 0.374 AC: 1297 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.5
DANN	Benign	0.62
PhyloP100		-0.011
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: rs2292982; hg19: chr16-85944823;