dbSNP rs16939945: IRF8:p.Asp144Asp (chr16-85911643-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001363908.1(IRF8):c.-75C>T variant causes a 5 prime UTR premature start codon gain 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_001363908.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -7.04

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 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_multiple_submitters_no_conflicts, 2 stars. Variant chr16-85911643-C-T is described in Lovd as [Benign].

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. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 4142 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF8	NM_002163.4 link	c.432C>T	p.Asp144Asp	synonymous_variant	Exon 4 of 9	ENST00000268638.10	NP_002154.1	Q02556

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF8	ENST00000268638.10 link	c.432C>T	p.Asp144Asp	synonymous_variant	Exon 4 of 9	1	NM_002163.4	ENSP00000268638.4		Q02556

Frequencies

GnomAD3 genomes

AF:

0.0272

AC:

4141

AN:

152178

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0224

AC XY:

3048

AN XY:

135878

show subpopulations

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.:

AF XY:

0.0260

AC XY:

18919

AN XY:

726984

show subpopulations

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.:

Cov.:

AF XY:

0.0269

AC XY:

2003

AN XY:

74468

show subpopulations

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.:

Bravo

AF:

0.0261

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.0277

EpiControl

AF:

0.0288

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over