Genetic Variant IRF8:c.448-256G>C (chr16-85912875-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002163.4(IRF8):c.448-256G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 152,088 control chromosomes in the GnomAD database, including 14,162 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.42 ( 14162 hom., cov: 33)

Consequence

IRF8
NM_002163.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.314

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Illumina
immunodeficiency 32B
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics

IRF8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002163.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IRF8	NM_002163.4	MANE Select	c.448-256G>C	intron	N/A	NP_002154.1	Q02556
IRF8	NM_001363907.1		c.478-256G>C	intron	N/A	NP_001350836.1
IRF8	NM_001363908.1		c.-60+1217G>C	intron	N/A	NP_001350837.1	H3BRT4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IRF8	ENST00000268638.10	TSL:1 MANE Select	c.448-256G>C	intron	N/A	ENSP00000268638.4	Q02556
IRF8	ENST00000564803.6	TSL:2	c.448-256G>C	intron	N/A	ENSP00000456992.2	Q02556
IRF8	ENST00000696887.1		c.448-256G>C	intron	N/A	ENSP00000512953.1	Q02556

Frequencies

GnomAD3 genomes

AF:

0.423

AC:

64235

AN:

151970

Hom.:

14118

Cov.:

show subpopulations

Gnomad AFR

AF:

0.542

Gnomad AMI

AF:

0.316

Gnomad AMR

AF:

0.333

Gnomad ASJ

AF:

0.345

Gnomad EAS

AF:

0.427

Gnomad SAS

AF:

0.282

Gnomad FIN

AF:

0.438

Gnomad MID

AF:

0.427

Gnomad NFE

AF:

0.383

Gnomad OTH

AF:

0.428

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.423

AC:

64333

AN:

152088

Hom.:

14162

Cov.:

AF XY:

0.421

AC XY:

31327

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.543

AC:

22515

AN:

41488

American (AMR)

AF:

0.333

AC:

5090

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.345

AC:

1198

AN:

3470

East Asian (EAS)

AF:

0.426

AC:

2210

AN:

5184

South Asian (SAS)

AF:

0.284

AC:

1366

AN:

4814

European-Finnish (FIN)

AF:

0.438

AC:

4633

AN:

10586

Middle Eastern (MID)

AF:

0.418

AC:

123

AN:

294

European-Non Finnish (NFE)

AF:

0.383

AC:

25991

AN:

67948

Other (OTH)

AF:

0.435

AC:

919

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1901

3801

5702

7602

9503

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

598

1196

1794

2392

2990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.251

Hom.:

559

Bravo

AF:

0.423

Asia WGS

AF:

0.399

AC:

1385

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

3.6

(source)

DANN

Benign

0.72

PhyloP100

0.31

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over