rs2270503

Positions:

• chr16-85921195-G-A
• chr16-85921195-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002163.4(IRF8):​c.1194G>A​(p.Pro398Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00481 in 1,614,174 control chromosomes in the GnomAD database, including 233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (211 hom.)
• Consequence: IRF8 NM_002163.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.839

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 16-85921195-G-A is Benign according to our data. Variant chr16-85921195-G-A is described in ClinVar as [Benign]. Clinvar id is 475386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.839 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.072 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRF8	NM_002163.4	c.1194G>A	p.Pro398Pro	synonymous_variant	9/9	ENST00000268638.10	NP_002154.1
IRF8	NM_001363907.1	c.1224G>A	p.Pro408Pro	synonymous_variant	9/9		NP_001350836.1
IRF8	NM_001363908.1	c.582G>A	p.Pro194Pro	synonymous_variant	7/7		NP_001350837.1
IRF8	XM_047434052.1	c.1224G>A	p.Pro408Pro	synonymous_variant	10/10		XP_047290008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRF8	ENST00000268638.10	c.1194G>A	p.Pro398Pro	synonymous_variant	9/9	1	NM_002163.4	ENSP00000268638.4

Frequencies

GnomAD3 genomes AF: 0.00742 AC: 1130 AN: 152202 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00306

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0438

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0475

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.0158 AC: 3982 AN: 251408 Hom.: 140 AF XY: 0.0134 AC XY: 1827 AN XY: 135904

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.0772

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0478

Gnomad SAS exome AF: 0.00990

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.0125

GnomAD4 exome AF: 0.00453 AC: 6624 AN: 1461854 Hom.: 211 Cov.: 31 AF XY: 0.00449 AC XY: 3263 AN XY: 727230

Gnomad4 AFR exome AF: 0.00323

Gnomad4 AMR exome AF: 0.0741

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0466

Gnomad4 SAS exome AF: 0.0101

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000719

Gnomad4 OTH exome AF: 0.00644

GnomAD4 genome AF: 0.00745 AC: 1135 AN: 152320 Hom.: 22 Cov.: 32 AF XY: 0.00820 AC XY: 611 AN XY: 74490

Gnomad4 AFR AF: 0.00310

Gnomad4 AMR AF: 0.0439

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0476

Gnomad4 SAS AF: 0.0124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00436 Hom.: 10

Bravo AF: 0.0115

Asia WGS AF: 0.0270 AC: 95 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 23% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported. -

Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency;C4016741:Immunodeficiency 32B Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.0
DANN	Benign	0.51

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: rs2270503; hg19: chr16-85954801;