Genetic Variant IRF4:c.*414G>A (chr6-408012-G-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_002460.4(IRF4):c.*414G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.821 in 292,132 control chromosomes in the GnomAD database, including 103,203 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 0.76 ( 47563 hom., cov: 32)

Exomes 𝑓: 0.89 ( 55640 hom. )

Consequence

IRF4
NM_002460.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.974

Publications

24 publications found

Variant links:

Genes affected

IRF4 (HGNC:6119): (interferon regulatory factor 4) The protein encoded by this gene belongs to the IRF (interferon regulatory factor) family of transcription factors, characterized by an unique tryptophan pentad repeat DNA-binding domain. The IRFs are important in the regulation of interferons in response to infection by virus, and in the regulation of interferon-inducible genes. This family member is lymphocyte specific and negatively regulates Toll-like-receptor (TLR) signaling that is central to the activation of innate and adaptive immune systems. A chromosomal translocation involving this gene and the IgH locus, t(6;14)(p25;q32), may be a cause of multiple myeloma. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2010]

IRF4 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=-0.85).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.908 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF4	NM_002460.4 link	c.*414G>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000380956.9	NP_002451.2	Q15306-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF4	ENST00000380956.9 link	c.*414G>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_002460.4	ENSP00000370343.4		Q15306-1
IRF4	ENST00000696871.1 link	c.*414G>A		downstream_gene_variant				ENSP00000512940.1		Q15306-2

Frequencies

GnomAD3 genomes

AF:

0.762

AC:

115847

AN:

152030

Hom.:

47566

Cov.:

show subpopulations

Gnomad AFR

AF:

0.426

Gnomad AMI

AF:

0.946

Gnomad AMR

AF:

0.829

Gnomad ASJ

AF:

0.928

Gnomad EAS

AF:

0.754

Gnomad SAS

AF:

0.922

Gnomad FIN

AF:

0.850

Gnomad MID

AF:

0.911

Gnomad NFE

AF:

0.914

Gnomad OTH

AF:

0.797

GnomAD4 exome

AF:

0.886

AC:

124065

AN:

139984

Hom.:

55640

Cov.:

AF XY:

0.893

AC XY:

60227

AN XY:

67438

show subpopulations

African (AFR)

AF:

0.431

AC:

1831

AN:

4246

American (AMR)

AF:

0.852

AC:

3832

AN:

4496

Ashkenazi Jewish (ASJ)

AF:

0.923

AC:

5992

AN:

6494

East Asian (EAS)

AF:

0.786

AC:

9658

AN:

12288

South Asian (SAS)

AF:

0.950

AC:

8683

AN:

9144

European-Finnish (FIN)

AF:

0.880

AC:

3567

AN:

4052

Middle Eastern (MID)

AF:

0.924

AC:

693

AN:

750

European-Non Finnish (NFE)

AF:

0.917

AC:

80915

AN:

88194

Other (OTH)

AF:

0.862

AC:

8894

AN:

10320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

650

1300

1950

2600

3250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

202

404

606

808

1010

<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:

0.762

AC:

115878

AN:

152148

Hom.:

47563

Cov.:

AF XY:

0.763

AC XY:

56788

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.427

AC:

17682

AN:

41458

American (AMR)

AF:

0.828

AC:

12669

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.928

AC:

3221

AN:

3472

East Asian (EAS)

AF:

0.753

AC:

3903

AN:

5180

South Asian (SAS)

AF:

0.924

AC:

4459

AN:

4828

European-Finnish (FIN)

AF:

0.850

AC:

9004

AN:

10592

Middle Eastern (MID)

AF:

0.901

AC:

265

AN:

294

European-Non Finnish (NFE)

AF:

0.914

AC:

62137

AN:

68010

Other (OTH)

AF:

0.794

AC:

1677

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1072

2145

3217

4290

5362

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

832

1664

2496

3328

4160

<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:

0.867

Hom.:

43693

Bravo

AF:

0.743

Asia WGS

AF:

0.770

AC:

2681

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.11

(source)

DANN

Benign

0.35

PhyloP100

-0.97

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