chr16-85902657-C-T

Variant names:

• chr16-85902657-C-T
• rs12924316
• NM_002163.4:c.-1-358C>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.-1-358C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 330,642 control chromosomes in the GnomAD database, including 4,579 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 (1883 hom., cov: 32)
  • Exomes 𝑓: 0.16 (2696 hom.)
• Consequence: IRF8 NM_002163.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.348
• Publications: 8 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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF8	NM_002163.4	c.-1-358C>T		intron_variant	Intron 1 of 8	ENST00000268638.10	NP_002154.1
IRF8	XM_047434052.1	c.-204C>T		5_prime_UTR_variant	Exon 2 of 10		XP_047290008.1
IRF8	NM_001363907.1	c.-204C>T		upstream_gene_variant			NP_001350836.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF8	ENST00000268638.10	c.-1-358C>T		intron_variant	Intron 1 of 8	1	NM_002163.4	ENSP00000268638.4

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21736 AN: 152142 Hom.: 1883 Cov.: 32

Gnomad AFR AF: 0.0442

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.255

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.169

GnomAD4 exome AF: 0.164 AC: 29217 AN: 178382 Hom.: 2696 Cov.: 0 AF XY: 0.159 AC XY: 15189 AN XY: 95520

African (AFR) AF: 0.0445 AC: 241 AN: 5412

American (AMR) AF: 0.177 AC: 1656 AN: 9374

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 715 AN: 4358

East Asian (EAS) AF: 0.254 AC: 2123 AN: 8372

South Asian (SAS) AF: 0.121 AC: 3780 AN: 31120

European-Finnish (FIN) AF: 0.152 AC: 1206 AN: 7942

Middle Eastern (MID) AF: 0.245 AC: 156 AN: 638

European-Non Finnish (NFE) AF: 0.173 AC: 17705 AN: 102116

Other (OTH) AF: 0.181 AC: 1635 AN: 9050

GnomAD4 genome AF: 0.143 AC: 21731 AN: 152260 Hom.: 1883 Cov.: 32 AF XY: 0.143 AC XY: 10627 AN XY: 74448

African (AFR) AF: 0.0442 AC: 1837 AN: 41568

American (AMR) AF: 0.176 AC: 2685 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 629 AN: 3468

East Asian (EAS) AF: 0.254 AC: 1315 AN: 5180

South Asian (SAS) AF: 0.142 AC: 686 AN: 4826

European-Finnish (FIN) AF: 0.174 AC: 1846 AN: 10608

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.180 AC: 12255 AN: 68010

Other (OTH) AF: 0.168 AC: 355 AN: 2114

Alfa AF: 0.0867 Hom.: 139

Bravo AF: 0.142

Asia WGS AF: 0.198 AC: 688 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.3
DANN	Benign	0.46
PhyloP100		-0.35
PromoterAI		0.014	Neutral
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: rs12924316; hg19: chr16-85936263;