rs16939967

Variant names:

• chr16-85915867-G-T
• rs16939967
• NM_002163.4:c.601+1347G>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.601+1347G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 152,168 control chromosomes in the GnomAD database, including 1,541 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 0.14 (1541 hom., cov: 33)
• Consequence: IRF8 NM_002163.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0560
• Publications: 10 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF8	NM_002163.4	c.601+1347G>T		intron_variant	Intron 6 of 8	ENST00000268638.10	NP_002154.1
IRF8	NM_001363907.1	c.631+1347G>T		intron_variant	Intron 6 of 8		NP_001350836.1
IRF8	NM_001363908.1	c.-12+1347G>T		intron_variant	Intron 4 of 6		NP_001350837.1
IRF8	XM_047434052.1	c.631+1347G>T		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.601+1347G>T		intron_variant	Intron 6 of 8	1	NM_002163.4	ENSP00000268638.4

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20719 AN: 152048 Hom.: 1539 Cov.: 33

Gnomad AFR AF: 0.0794

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.154

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

GnomAD4 genome AF: 0.136 AC: 20726 AN: 152168 Hom.: 1541 Cov.: 33 AF XY: 0.136 AC XY: 10144 AN XY: 74378

African (AFR) AF: 0.0795 AC: 3301 AN: 41542

American (AMR) AF: 0.123 AC: 1883 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 535 AN: 3468

East Asian (EAS) AF: 0.229 AC: 1183 AN: 5162

South Asian (SAS) AF: 0.134 AC: 648 AN: 4818

European-Finnish (FIN) AF: 0.172 AC: 1818 AN: 10578

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.160 AC: 10900 AN: 67980

Other (OTH) AF: 0.153 AC: 323 AN: 2112

Alfa AF: 0.152 Hom.: 6853

Bravo AF: 0.132

Asia WGS AF: 0.187 AC: 648 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.1
DANN	Benign	0.90
PhyloP100		0.056
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: rs16939967; hg19: chr16-85949473;