rs147080359

chr16-85918628-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_002163.4(IRF8):c.813C>T(p.Phe271=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00397 in 1,608,418 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (25 hom.)
• Consequence: IRF8 NM_002163.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.152

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 16-85918628-C-T is Benign according to our data. Variant chr16-85918628-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 542147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-85918628-C-T is described in Lovd as [Likely_benign]. Variant chr16-85918628-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.152 with no splicing effect.
• BS2: High AC in GnomAd at 542 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF8	NM_002163.4	c.813C>T	p.Phe271=	synonymous_variant	7/9	ENST00000268638.10
IRF8	NM_001363907.1	c.843C>T	p.Phe281=	synonymous_variant	7/9
IRF8	NM_001363908.1	c.201C>T	p.Phe67=	synonymous_variant	5/7
IRF8	XM_047434052.1	c.843C>T	p.Phe281=	synonymous_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF8	ENST00000268638.10	c.813C>T	p.Phe271=	synonymous_variant	7/9	1	NM_002163.4	P1

Frequencies

GnomAD3 genomes AF: 0.00356 AC: 542 AN: 152264 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0168

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00412

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00340 AC: 813 AN: 239020 Hom.: 6 AF XY: 0.00328 AC XY: 431 AN XY: 131354

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000226

Gnomad SAS exome AF: 0.000197

Gnomad FIN exome AF: 0.0174

Gnomad NFE exome AF: 0.00386

Gnomad OTH exome AF: 0.00390

GnomAD4 exome AF: 0.00402 AC: 5850 AN: 1456036 Hom.: 25 Cov.: 31 AF XY: 0.00397 AC XY: 2876 AN XY: 724628

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00175

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000907

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.0164

Gnomad4 NFE exome AF: 0.00422

Gnomad4 OTH exome AF: 0.00352

GnomAD4 genome AF: 0.00356 AC: 542 AN: 152382 Hom.: 2 Cov.: 33 AF XY: 0.00396 AC XY: 295 AN XY: 74522

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0168

Gnomad4 NFE AF: 0.00412

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00319 Hom.: 0

Bravo AF: 0.00243

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00382

EpiControl AF: 0.00267

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	IRF8: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	9.1
Dann	Benign	0.78

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: rs147080359; hg19: chr16-85952234; COSMIC: COSV51897701; COSMIC: COSV51897701;