Genetic Variant IRF8:c.*783C>T (chr16-85922065-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.*783C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 152,172 control chromosomes in the GnomAD database, including 12,308 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 0.40 ( 12292 hom., cov: 33)

Exomes 𝑓: 0.38 ( 16 hom. )

Consequence

IRF8
NM_002163.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.408

Publications

36 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:

Genome browser will be placed here

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=-0.88).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.444 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.*783C>T	3_prime_UTR	Exon 9 of 9	NP_002154.1	Q02556
IRF8	NM_001363907.1		c.*783C>T	3_prime_UTR	Exon 9 of 9	NP_001350836.1
IRF8	NM_001363908.1		c.*783C>T	3_prime_UTR	Exon 7 of 7	NP_001350837.1	H3BRT4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IRF8	ENST00000268638.10	TSL:1 MANE Select	c.*783C>T	3_prime_UTR	Exon 9 of 9	ENSP00000268638.4	Q02556
IRF8	ENST00000564803.6	TSL:2	c.*783C>T	3_prime_UTR	Exon 9 of 9	ENSP00000456992.2	Q02556
IRF8	ENST00000696887.1		c.*783C>T	3_prime_UTR	Exon 9 of 9	ENSP00000512953.1	Q02556

Frequencies

GnomAD3 genomes

AF:

0.397

AC:

60291

AN:

151896

Hom.:

12261

Cov.:

show subpopulations

Gnomad AFR

AF:

0.449

Gnomad AMI

AF:

0.260

Gnomad AMR

AF:

0.315

Gnomad ASJ

AF:

0.344

Gnomad EAS

AF:

0.389

Gnomad SAS

AF:

0.245

Gnomad FIN

AF:

0.480

Gnomad MID

AF:

0.396

Gnomad NFE

AF:

0.387

Gnomad OTH

AF:

0.386

GnomAD4 exome

AF:

0.380

AC:

AN:

158

Hom.:

Cov.:

AF XY:

0.386

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.404

AC:

AN:

136

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.214

AC:

AN:

Other (OTH)

AF:

0.333

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.397

AC:

60376

AN:

152014

Hom.:

12292

Cov.:

AF XY:

0.396

AC XY:

29384

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.450

AC:

18646

AN:

41448

American (AMR)

AF:

0.315

AC:

4805

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.344

AC:

1194

AN:

3468

East Asian (EAS)

AF:

0.390

AC:

2019

AN:

5182

South Asian (SAS)

AF:

0.246

AC:

1185

AN:

4816

European-Finnish (FIN)

AF:

0.480

AC:

5065

AN:

10556

Middle Eastern (MID)

AF:

0.388

AC:

114

AN:

294

European-Non Finnish (NFE)

AF:

0.387

AC:

26282

AN:

67972

Other (OTH)

AF:

0.393

AC:

829

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1872

3744

5616

7488

9360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

574

1148

1722

2296

2870

<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:

0.385

Hom.:

47425

Bravo

AF:

0.390

Asia WGS

AF:

0.350

AC:

1216

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

2.5

(source)

DANN

Benign

0.73

PhyloP100

-0.41

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over