Genetic Variant IRF8:c.448-720C>A (chr16-85912411-C-A) – 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.448-720C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.068 in 152,232 control chromosomes in the GnomAD database, including 546 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 0.068 ( 546 hom., cov: 33)

Consequence

IRF8
NM_002163.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.175

Publications

5 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=-0.83).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
IRF8	NM_002163.4 link	c.448-720C>A	intron_variant	Intron 4 of 8	ENST00000268638.10	NP_002154.1	Q02556
IRF8	NM_001363907.1 link	c.478-720C>A	intron_variant	Intron 4 of 8		NP_001350836.1
IRF8	NM_001363908.1 link	c.-60+753C>A	intron_variant	Intron 3 of 6		NP_001350837.1
IRF8	XM_047434052.1 link	c.478-720C>A	intron_variant	Intron 5 of 9		XP_047290008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF8	ENST00000268638.10 link	c.448-720C>A		intron_variant	Intron 4 of 8	1	NM_002163.4	ENSP00000268638.4		Q02556

Frequencies

GnomAD3 genomes

AF:

0.0679

AC:

10325

AN:

152114

Hom.:

543

Cov.:

show subpopulations

Gnomad AFR

AF:

0.129

Gnomad AMI

AF:

0.0526

Gnomad AMR

AF:

0.0487

Gnomad ASJ

AF:

0.0363

Gnomad EAS

AF:

0.178

Gnomad SAS

AF:

0.0342

Gnomad FIN

AF:

0.0543

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0331

Gnomad OTH

AF:

0.0717

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

GnomAD4 genome

AF:

0.0680

AC:

10347

AN:

152232

Hom.:

546

Cov.:

AF XY:

0.0684

AC XY:

5090

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.128

AC:

5333

AN:

41506

American (AMR)

AF:

0.0486

AC:

744

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0363

AC:

126

AN:

3472

East Asian (EAS)

AF:

0.178

AC:

923

AN:

5192

South Asian (SAS)

AF:

0.0344

AC:

166

AN:

4824

European-Finnish (FIN)

AF:

0.0543

AC:

575

AN:

10598

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0331

AC:

2252

AN:

68020

Other (OTH)

AF:

0.0752

AC:

159

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

483

965

1448

1930

2413

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<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:

0.0744

Hom.:

246

Bravo

AF:

0.0719

Asia WGS

AF:

0.0960

AC:

332

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

7.0

(source)

DANN

Benign

0.51

PhyloP100

0.17

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over