rs2292980

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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

Gnomad4 AFR exome AF: 0.485

Gnomad4 AMR exome AF: 0.361

Gnomad4 ASJ exome AF: 0.333

Gnomad4 EAS exome AF: 0.434

Gnomad4 SAS exome AF: 0.267

Gnomad4 FIN exome AF: 0.395

Gnomad4 NFE exome AF: 0.339

Gnomad4 OTH exome AF: 0.373

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

Gnomad4 AFR AF: 0.486

Gnomad4 AMR AF: 0.340

Gnomad4 ASJ AF: 0.334

Gnomad4 EAS AF: 0.454

Gnomad4 SAS AF: 0.267

Gnomad4 FIN AF: 0.403

Gnomad4 NFE AF: 0.343

Gnomad4 OTH AF: 0.402

Alfa AF: 0.370 Hom.: 2167

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2292980; hg19: chr16-85945076; COSMIC: COSV51897129; COSMIC: COSV51897129;