dbSNP rs566756778: IRF4:p.Arg25Arg (chr6-393227-C-G) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP7

The NM_002460.4(IRF4):c.75C>G(p.Arg25Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,418,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R25R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

IRF4
NM_002460.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.651

Publications

0 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 Gene-Disease associations (from GenCC):

combined immunodeficiency
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

IRF4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

BP7

Synonymous conserved (PhyloP=0.651 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002460.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IRF4	NM_002460.4	MANE Select	c.75C>G	p.Arg25Arg	synonymous	Exon 2 of 9	NP_002451.2	Q15306-1
IRF4	NM_001195286.2		c.75C>G	p.Arg25Arg	synonymous	Exon 2 of 9	NP_001182215.1	Q15306-2
IRF4	NR_046000.3		n.188C>G		non_coding_transcript_exon	Exon 2 of 10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IRF4	ENST00000380956.9	TSL:1 MANE Select	c.75C>G	p.Arg25Arg	synonymous	Exon 2 of 9	ENSP00000370343.4	Q15306-1
IRF4	ENST00000866554.1		c.75C>G	p.Arg25Arg	synonymous	Exon 2 of 9	ENSP00000536613.1
IRF4	ENST00000696871.1		c.75C>G	p.Arg25Arg	synonymous	Exon 2 of 9	ENSP00000512940.1	Q15306-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.05e-7

AC:

AN:

1418904

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

701660

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32664

American (AMR)

AF:

0.00

AC:

AN:

38078

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25346

East Asian (EAS)

AF:

0.00

AC:

AN:

37576

South Asian (SAS)

AF:

0.0000124

AC:

AN:

80584

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50140

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1089994

Other (OTH)

AF:

0.00

AC:

AN:

58816

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over