Genetic Variant IRF8:p.Cys138Cys (chr16-85911625-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002163.4(IRF8):c.414C>T(p.Cys138Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,613,544 control chromosomes in the GnomAD database, including 15,197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1382 hom., cov: 33)

Exomes 𝑓: 0.13 ( 13815 hom. )

Consequence

IRF8
NM_002163.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.575

Publications

17 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 16-85911625-C-T is Benign according to our data. Variant chr16-85911625-C-T is described in ClinVar as Benign. ClinVar VariationId is 1168657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.575 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.14 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	HGVSp	Effect	Exon Rank	Protein	UniProt
IRF8	NM_002163.4	MANE Select	c.414C>T	p.Cys138Cys	synonymous	Exon 4 of 9	NP_002154.1	Q02556
IRF8	NM_001363907.1		c.444C>T	p.Cys148Cys	synonymous	Exon 4 of 9	NP_001350836.1
IRF8	NM_001363908.1		c.-93C>T		5_prime_UTR	Exon 3 of 7	NP_001350837.1	H3BRT4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IRF8	ENST00000268638.10	TSL:1 MANE Select	c.414C>T	p.Cys138Cys	synonymous	Exon 4 of 9	ENSP00000268638.4	Q02556
IRF8	ENST00000564803.6	TSL:2	c.414C>T	p.Cys138Cys	synonymous	Exon 4 of 9	ENSP00000456992.2	Q02556
IRF8	ENST00000696887.1		c.414C>T	p.Cys138Cys	synonymous	Exon 4 of 9	ENSP00000512953.1	Q02556

Frequencies

GnomAD3 genomes

AF:

0.131

AC:

19992

AN:

152098

Hom.:

1377

Cov.:

show subpopulations

Gnomad AFR

AF:

0.133

Gnomad AMI

AF:

0.137

Gnomad AMR

AF:

0.110

Gnomad ASJ

AF:

0.115

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.0915

Gnomad FIN

AF:

0.176

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.142

Gnomad OTH

AF:

0.123

GnomAD2 exomes

AF:

0.124

AC:

31230

AN:

251328

AF XY:

0.124

show subpopulations

Gnomad AFR exome

AF:

0.135

Gnomad AMR exome

AF:

0.118

Gnomad ASJ exome

AF:

0.129

Gnomad EAS exome

AF:

0.00163

Gnomad FIN exome

AF:

0.180

Gnomad NFE exome

AF:

0.138

Gnomad OTH exome

AF:

0.120

GnomAD4 exome

AF:

0.133

AC:

194822

AN:

1461328

Hom.:

13815

Cov.:

AF XY:

0.133

AC XY:

96517

AN XY:

726956

show subpopulations

African (AFR)

AF:

0.130

AC:

4355

AN:

33462

American (AMR)

AF:

0.116

AC:

5186

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.127

AC:

3324

AN:

26126

East Asian (EAS)

AF:

0.000983

AC:

AN:

39662

South Asian (SAS)

AF:

0.107

AC:

9192

AN:

86240

European-Finnish (FIN)

AF:

0.182

AC:

9712

AN:

53340

Middle Eastern (MID)

AF:

0.0579

AC:

334

AN:

5764

European-Non Finnish (NFE)

AF:

0.139

AC:

154858

AN:

1111648

Other (OTH)

AF:

0.130

AC:

7822

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

8867

17734

26601

35468

44335

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5412

10824

16236

21648

27060

<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:

0.131

AC:

20016

AN:

152216

Hom.:

1382

Cov.:

AF XY:

0.131

AC XY:

9714

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.133

AC:

5531

AN:

41522

American (AMR)

AF:

0.111

AC:

1692

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.115

AC:

398

AN:

3472

East Asian (EAS)

AF:

0.00116

AC:

AN:

5182

South Asian (SAS)

AF:

0.0914

AC:

441

AN:

4824

European-Finnish (FIN)

AF:

0.176

AC:

1865

AN:

10594

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.142

AC:

9680

AN:

68010

Other (OTH)

AF:

0.125

AC:

264

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

895

1791

2686

3582

4477

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

222

444

666

888

1110

<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:

0.127

Hom.:

1900

Bravo

AF:

0.127

Asia WGS

AF:

0.0740

AC:

256

AN:

3478

EpiCase

AF:

0.130

EpiControl

AF:

0.125

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Immunodeficiency 32B (1)

Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency (1)

Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency;C4751209:Immunodeficiency 32B (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

1.2

(source)

DANN

Benign

0.37

PhyloP100

-0.57

Mutation Taster

=98/2

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