Genetic Variant IRF3:c.983-305A>G (chr19-49661133-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001571.6(IRF3):c.983-305A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 388,822 control chromosomes in the GnomAD database, including 44,414 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 0.52 ( 23755 hom., cov: 33)

Exomes 𝑓: 0.40 ( 20659 hom. )

Consequence

IRF3
NM_001571.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.25

Publications

13 publications found

Variant links:

Genes affected

IRF3 (HGNC:6118): (interferon regulatory factor 3) This gene encodes a member of the interferon regulatory transcription factor (IRF) family. The encoded protein is found in an inactive cytoplasmic form that upon serine/threonine phosphorylation forms a complex with CREBBP. This complex translocates to the nucleus and activates the transcription of interferons alpha and beta, as well as other interferon-induced genes. The protein plays an important role in the innate immune response against DNA and RNA viruses. Mutations in this gene are associated with Encephalopathy, acute, infection-induced, herpes-specific, 7. [provided by RefSeq, Sep 2020]

IRF3 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=-0.91).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.835 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF3	NM_001571.6 link	c.983-305A>G		intron_variant	Intron 6 of 7	ENST00000377139.8	NP_001562.1	Q14653-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF3	ENST00000377139.8 link	c.983-305A>G		intron_variant	Intron 6 of 7	1	NM_001571.6	ENSP00000366344.3		Q14653-1

Frequencies

GnomAD3 genomes

AF:

0.518

AC:

78702

AN:

151988

Hom.:

23696

Cov.:

show subpopulations

Gnomad AFR

AF:

0.842

Gnomad AMI

AF:

0.420

Gnomad AMR

AF:

0.485

Gnomad ASJ

AF:

0.397

Gnomad EAS

AF:

0.358

Gnomad SAS

AF:

0.553

Gnomad FIN

AF:

0.286

Gnomad MID

AF:

0.522

Gnomad NFE

AF:

0.382

Gnomad OTH

AF:

0.481

GnomAD4 exome

AF:

0.401

AC:

94878

AN:

236716

Hom.:

20659

AF XY:

0.405

AC XY:

49798

AN XY:

122942

show subpopulations

African (AFR)

AF:

0.840

AC:

5193

AN:

6180

American (AMR)

AF:

0.473

AC:

3476

AN:

7344

Ashkenazi Jewish (ASJ)

AF:

0.386

AC:

3116

AN:

8078

East Asian (EAS)

AF:

0.366

AC:

5318

AN:

14526

South Asian (SAS)

AF:

0.511

AC:

11309

AN:

22142

European-Finnish (FIN)

AF:

0.306

AC:

4656

AN:

15198

Middle Eastern (MID)

AF:

0.502

AC:

587

AN:

1170

European-Non Finnish (NFE)

AF:

0.373

AC:

54935

AN:

147194

Other (OTH)

AF:

0.422

AC:

6288

AN:

14884

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

2565

5130

7694

10259

12824

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

294

588

882

1176

1470

<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:

0.518

AC:

78815

AN:

152106

Hom.:

23755

Cov.:

AF XY:

0.512

AC XY:

38056

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.842

AC:

34973

AN:

41512

American (AMR)

AF:

0.485

AC:

7410

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.397

AC:

1377

AN:

3472

East Asian (EAS)

AF:

0.358

AC:

1845

AN:

5156

South Asian (SAS)

AF:

0.551

AC:

2657

AN:

4822

European-Finnish (FIN)

AF:

0.286

AC:

3033

AN:

10590

Middle Eastern (MID)

AF:

0.514

AC:

151

AN:

294

European-Non Finnish (NFE)

AF:

0.382

AC:

25966

AN:

67962

Other (OTH)

AF:

0.483

AC:

1020

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1658

3317

4975

6634

8292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

650

1300

1950

2600

3250

<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:

0.435

Hom.:

46479

Bravo

AF:

0.544

Asia WGS

AF:

0.539

AC:

1870

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.47

(source)

DANN

Benign

0.63

PhyloP100

-1.3

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over