Genetic Variant IRF8:c.175-822C>T (chr16-85908168-C-T) – 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.175-822C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 152,098 control chromosomes in the GnomAD database, including 14,490 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 ( 14490 hom., cov: 33)

Consequence

IRF8
NM_002163.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.712

Publications

12 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=-0.87).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.608 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.175-822C>T	intron	N/A	NP_002154.1	Q02556
IRF8	NM_001363907.1		c.205-822C>T	intron	N/A	NP_001350836.1
IRF8	NM_001363908.1		c.-332-822C>T	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.175-822C>T	intron	N/A	ENSP00000268638.4	Q02556
IRF8	ENST00000563180.1	TSL:1	c.175-822C>T	intron	N/A	ENSP00000458047.1	H3BVC2
IRF8	ENST00000564803.6	TSL:2	c.175-822C>T	intron	N/A	ENSP00000456992.2	Q02556

Frequencies

GnomAD3 genomes

AF:

0.418

AC:

63512

AN:

151980

Hom.:

14436

Cov.:

show subpopulations

Gnomad AFR

AF:

0.613

Gnomad AMI

AF:

0.245

Gnomad AMR

AF:

0.354

Gnomad ASJ

AF:

0.372

Gnomad EAS

AF:

0.322

Gnomad SAS

AF:

0.267

Gnomad FIN

AF:

0.401

Gnomad MID

AF:

0.392

Gnomad NFE

AF:

0.339

Gnomad OTH

AF:

0.415

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

GnomAD4 genome

AF:

0.418

AC:

63624

AN:

152098

Hom.:

14490

Cov.:

AF XY:

0.416

AC XY:

30954

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.614

AC:

25456

AN:

41462

American (AMR)

AF:

0.354

AC:

5413

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.372

AC:

1292

AN:

3470

East Asian (EAS)

AF:

0.321

AC:

1664

AN:

5180

South Asian (SAS)

AF:

0.268

AC:

1291

AN:

4824

European-Finnish (FIN)

AF:

0.401

AC:

4237

AN:

10566

Middle Eastern (MID)

AF:

0.381

AC:

112

AN:

294

European-Non Finnish (NFE)

AF:

0.339

AC:

23046

AN:

67998

Other (OTH)

AF:

0.421

AC:

890

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1840

3679

5519

7358

9198

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

580

1160

1740

2320

2900

<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:

0.365

Hom.:

8352

Bravo

AF:

0.427

Asia WGS

AF:

0.363

AC:

1259

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.61

(source)

DANN

Benign

0.47

PhyloP100

-0.71

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