rs16939945

chr16-85911643-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_002163.4(IRF8):c.432C>T(p.Asp144=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0265 in 1,613,594 control chromosomes in the GnomAD database, including 653 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.027 (63 hom., cov: 33)
  • Exomes 𝑓: 0.026 (590 hom.)
• Consequence: IRF8 NM_002163.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -7.04

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=-0.77).
• BP6: Variant 16-85911643-C-T is Benign according to our data. Variant chr16-85911643-C-T is described in ClinVar as [Benign]. Clinvar id is 475391.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-85911643-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-7.05 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0272 (4142/152296) while in subpopulation AFR AF= 0.0321 (1332/41538). AF 95% confidence interval is 0.0306. There are 63 homozygotes in gnomad4. There are 2003 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 4141 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF8	NM_002163.4	c.432C>T	p.Asp144=	synonymous_variant	4/9	ENST00000268638.10
IRF8	NM_001363907.1	c.462C>T	p.Asp154=	synonymous_variant	4/9
IRF8	XM_047434052.1	c.462C>T	p.Asp154=	synonymous_variant	5/10
IRF8	NM_001363908.1	c.-75C>T		5_prime_UTR_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF8	ENST00000268638.10	c.432C>T	p.Asp144=	synonymous_variant	4/9	1	NM_002163.4	P1

Frequencies

GnomAD3 genomes AF: 0.0272 AC: 4141 AN: 152178 Hom.: 63 Cov.: 33

Gnomad AFR AF: 0.0321

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.0333

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0290

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0222 AC: 5590 AN: 251368 Hom.: 78 AF XY: 0.0224 AC XY: 3048 AN XY: 135878

Gnomad AFR exome AF: 0.0328

Gnomad AMR exome AF: 0.0127

Gnomad ASJ exome AF: 0.00913

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.0139

Gnomad FIN exome AF: 0.0317

Gnomad NFE exome AF: 0.0285

Gnomad OTH exome AF: 0.0270

GnomAD4 exome AF: 0.0264 AC: 38642 AN: 1461298 Hom.: 590 Cov.: 32 AF XY: 0.0260 AC XY: 18919 AN XY: 726984

Gnomad4 AFR exome AF: 0.0318

Gnomad4 AMR exome AF: 0.0132

Gnomad4 ASJ exome AF: 0.00934

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0137

Gnomad4 FIN exome AF: 0.0319

Gnomad4 NFE exome AF: 0.0289

Gnomad4 OTH exome AF: 0.0252

GnomAD4 genome AF: 0.0272 AC: 4142 AN: 152296 Hom.: 63 Cov.: 33 AF XY: 0.0269 AC XY: 2003 AN XY: 74468

Gnomad4 AFR AF: 0.0321

Gnomad4 AMR AF: 0.0183

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0124

Gnomad4 FIN AF: 0.0333

Gnomad4 NFE AF: 0.0290

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.0275 Hom.: 51

Bravo AF: 0.0261

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0277

EpiControl AF: 0.0288

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.096
Dann	Benign	0.40

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: rs16939945; hg19: chr16-85945249; COSMIC: COSV51898098; COSMIC: COSV51898098;