rs16939945

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_002163.4(IRF8):c.432C>T(p.Asp144Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0265 in 1,613,594 control chromosomes in the GnomAD database, including 653 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 63 hom., cov: 33)

Exomes 𝑓: 0.026 ( 590 hom. )

Consequence

IRF8
NM_002163.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -7.04

Publications

13 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=-0.77).

BP6

Variant 16-85911643-C-T is Benign according to our data. Variant chr16-85911643-C-T is described in ClinVar as Benign. ClinVar VariationId is 475391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-7.05 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0272 (4142/152296) while in subpopulation AFR AF = 0.0321 (1332/41538). AF 95% confidence interval is 0.0306. There are 63 homozygotes in GnomAd4. There are 2003 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 63 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF8	NM_002163.4 link	c.432C>T	p.Asp144Asp	synonymous_variant	Exon 4 of 9	ENST00000268638.10	NP_002154.1	Q02556

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF8	ENST00000268638.10 link	c.432C>T	p.Asp144Asp	synonymous_variant	Exon 4 of 9	1	NM_002163.4	ENSP00000268638.4		Q02556

Frequencies

GnomAD3 genomes

AF:

0.0272

AC:

4141

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0321

Gnomad AMI

AF:

0.0471

Gnomad AMR

AF:

0.0183

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0122

Gnomad FIN

AF:

0.0333

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0290

Gnomad OTH

AF:

0.0258

GnomAD2 exomes

AF:

0.0222

AC:

5590

AN:

251368

AF XY:

0.0224

show subpopulations

Gnomad AFR exome

AF:

0.0328

Gnomad AMR exome

AF:

0.0127

Gnomad ASJ exome

AF:

0.00913

Gnomad EAS exome

AF:

0.000544

Gnomad FIN exome

AF:

0.0317

Gnomad NFE exome

AF:

0.0285

Gnomad OTH exome

AF:

0.0270

GnomAD4 exome

AF:

0.0264

AC:

38642

AN:

1461298

Hom.:

590

Cov.:

AF XY:

0.0260

AC XY:

18919

AN XY:

726984

show subpopulations

African (AFR)

AF:

0.0318

AC:

1064

AN:

33458

American (AMR)

AF:

0.0132

AC:

589

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00934

AC:

244

AN:

26128

East Asian (EAS)

AF:

0.000227

AC:

AN:

39692

South Asian (SAS)

AF:

0.0137

AC:

1182

AN:

86230

European-Finnish (FIN)

AF:

0.0319

AC:

1704

AN:

53350

Middle Eastern (MID)

AF:

0.0285

AC:

164

AN:

5756

European-Non Finnish (NFE)

AF:

0.0289

AC:

32164

AN:

1111596

Other (OTH)

AF:

0.0252

AC:

1522

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

1853

3706

5558

7411

9264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1190

2380

3570

4760

5950

<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:

0.0272

AC:

4142

AN:

152296

Hom.:

Cov.:

AF XY:

0.0269

AC XY:

2003

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0321

AC:

1332

AN:

41538

American (AMR)

AF:

0.0183

AC:

280

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.0124

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0333

AC:

353

AN:

10608

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0290

AC:

1975

AN:

68030

Other (OTH)

AF:

0.0255

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

210

420

631

841

1051

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0275

Hom.:

134

Bravo

AF:

0.0261

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.0277

EpiControl

AF:

0.0288

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.096

(source)

DANN

Benign

0.40

PhyloP100

-7.0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over