6-410493-A-G

Variant names:

• chr6-410493-A-G
• rs1877175
• NM_002460.4:c.*2895A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002460.4(IRF4):​c.*2895A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.793 in 228,406 control chromosomes in the GnomAD database, including 72,070 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 0.79 (47478 hom., cov: 32)
  • Exomes 𝑓: 0.80 (24592 hom.)
• Consequence: IRF4 NM_002460.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.137
• Publications: 21 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.822 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF4	NM_002460.4	MANE Select	c.*2895A>G		3_prime_UTR	Exon 9 of 9	NP_002451.2	Q15306-1
	IRF4	NM_001195286.2		c.*2895A>G		3_prime_UTR	Exon 9 of 9	NP_001182215.1	Q15306-2
	IRF4	NR_046000.3		n.4495A>G		non_coding_transcript_exon	Exon 10 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF4	ENST00000380956.9	TSL:1 MANE Select	c.*2895A>G		3_prime_UTR	Exon 9 of 9	ENSP00000370343.4	Q15306-1
	IRF4	ENST00000866553.1		c.*2895A>G		3_prime_UTR	Exon 8 of 8	ENSP00000536612.1

Frequencies

GnomAD3 genomes AF: 0.788 AC: 119763 AN: 152024 Hom.: 47434 Cov.: 32

Gnomad AFR AF: 0.738

Gnomad AMI AF: 0.647

Gnomad AMR AF: 0.826

Gnomad ASJ AF: 0.782

Gnomad EAS AF: 0.842

Gnomad SAS AF: 0.795

Gnomad FIN AF: 0.854

Gnomad MID AF: 0.771

Gnomad NFE AF: 0.797

Gnomad OTH AF: 0.767

GnomAD4 exome AF: 0.802 AC: 61191 AN: 76264 Hom.: 24592 Cov.: 0 AF XY: 0.804 AC XY: 28313 AN XY: 35210

African (AFR) AF: 0.734 AC: 2670 AN: 3638

American (AMR) AF: 0.817 AC: 1910 AN: 2338

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 3774 AN: 4812

East Asian (EAS) AF: 0.857 AC: 9398 AN: 10970

South Asian (SAS) AF: 0.775 AC: 513 AN: 662

European-Finnish (FIN) AF: 0.750 AC: 42 AN: 56

Middle Eastern (MID) AF: 0.768 AC: 361 AN: 470

European-Non Finnish (NFE) AF: 0.799 AC: 37484 AN: 46938

Other (OTH) AF: 0.790 AC: 5039 AN: 6380

GnomAD4 genome AF: 0.788 AC: 119867 AN: 152142 Hom.: 47478 Cov.: 32 AF XY: 0.792 AC XY: 58867 AN XY: 74372

African (AFR) AF: 0.738 AC: 30643 AN: 41512

American (AMR) AF: 0.827 AC: 12637 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 2713 AN: 3468

East Asian (EAS) AF: 0.843 AC: 4364 AN: 5176

South Asian (SAS) AF: 0.795 AC: 3836 AN: 4824

European-Finnish (FIN) AF: 0.854 AC: 9037 AN: 10576

Middle Eastern (MID) AF: 0.750 AC: 219 AN: 292

European-Non Finnish (NFE) AF: 0.797 AC: 54207 AN: 67988

Other (OTH) AF: 0.769 AC: 1621 AN: 2108

Alfa AF: 0.791 Hom.: 185808

Bravo AF: 0.781

Asia WGS AF: 0.826 AC: 2872 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.6
DANN	Benign	0.70
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1877175; hg19: chr6-410493;