rs2292980

Variant names:

• chr16-85911470-T-C
• rs2292980
• NM_002163.4:c.359-100T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002163.4(IRF8):​c.359-100T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 1,007,118 control chromosomes in the GnomAD database, including 64,415 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.39 (11797 hom., cov: 33)
  • Exomes 𝑓: 0.35 (52618 hom.)
• Consequence: IRF8 NM_002163.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.25
• Publications: 20 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-85911470-T-C is Benign according to our data. Variant chr16-85911470-T-C is described in ClinVar as Benign. ClinVar VariationId is 2688501.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF8	NM_002163.4	c.359-100T>C		intron_variant	Intron 3 of 8	ENST00000268638.10	NP_002154.1
IRF8	NM_001363907.1	c.389-100T>C		intron_variant	Intron 3 of 8		NP_001350836.1
IRF8	NM_001363908.1	c.-148-100T>C		intron_variant	Intron 2 of 6		NP_001350837.1
IRF8	XM_047434052.1	c.389-100T>C		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.359-100T>C		intron_variant	Intron 3 of 8	1	NM_002163.4	ENSP00000268638.4

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58801 AN: 151968 Hom.: 11748 Cov.: 33

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.454

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.343

Gnomad OTH AF: 0.395

GnomAD4 exome AF: 0.346 AC: 296166 AN: 855032 Hom.: 52618 AF XY: 0.343 AC XY: 152402 AN XY: 444618

African (AFR) AF: 0.485 AC: 10581 AN: 21806

American (AMR) AF: 0.361 AC: 13689 AN: 37962

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 7111 AN: 21328

East Asian (EAS) AF: 0.434 AC: 15167 AN: 34956

South Asian (SAS) AF: 0.267 AC: 18766 AN: 70242

European-Finnish (FIN) AF: 0.395 AC: 19306 AN: 48882

Middle Eastern (MID) AF: 0.387 AC: 1803 AN: 4656

European-Non Finnish (NFE) AF: 0.339 AC: 194853 AN: 575266

Other (OTH) AF: 0.373 AC: 14890 AN: 39934

GnomAD4 genome AF: 0.387 AC: 58901 AN: 152086 Hom.: 11797 Cov.: 33 AF XY: 0.387 AC XY: 28783 AN XY: 74346

African (AFR) AF: 0.486 AC: 20144 AN: 41470

American (AMR) AF: 0.340 AC: 5204 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 1158 AN: 3468

East Asian (EAS) AF: 0.454 AC: 2346 AN: 5168

South Asian (SAS) AF: 0.267 AC: 1290 AN: 4824

European-Finnish (FIN) AF: 0.403 AC: 4253 AN: 10564

Middle Eastern (MID) AF: 0.404 AC: 118 AN: 292

European-Non Finnish (NFE) AF: 0.343 AC: 23293 AN: 67990

Other (OTH) AF: 0.402 AC: 850 AN: 2114

Alfa AF: 0.401 Hom.: 3861

Bravo AF: 0.391

Asia WGS AF: 0.411 AC: 1425 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 19. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.26
DANN	Benign	0.37
PhyloP100		-1.3
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: rs2292980; hg19: chr16-85945076; COSMIC: COSV51897129; COSMIC: COSV51897129;