6-408246-T-C

Position:

• chr6-408246-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002460.4(IRF4):​c.*648T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 231,996 control chromosomes in the GnomAD database, including 8,347 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 0.28 (5763 hom., cov: 33)
  • Exomes 𝑓: 0.25 (2584 hom.)
• Consequence: IRF4 NM_002460.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.321

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.312 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRF4	NM_002460.4	c.*648T>C		3_prime_UTR_variant	9/9	ENST00000380956.9	NP_002451.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRF4	ENST00000380956.9	c.*648T>C		3_prime_UTR_variant	9/9	1	NM_002460.4	ENSP00000370343	P4

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41958 AN: 151966 Hom.: 5764 Cov.: 33

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.270

GnomAD4 exome AF: 0.250 AC: 19997 AN: 79912 Hom.: 2584 Cov.: 0 AF XY: 0.253 AC XY: 9327 AN XY: 36904

Gnomad4 AFR exome AF: 0.296

Gnomad4 AMR exome AF: 0.254

Gnomad4 ASJ exome AF: 0.201

Gnomad4 EAS exome AF: 0.333

Gnomad4 SAS exome AF: 0.277

Gnomad4 FIN exome AF: 0.275

Gnomad4 NFE exome AF: 0.234

Gnomad4 OTH exome AF: 0.232

GnomAD4 genome AF: 0.276 AC: 41986 AN: 152084 Hom.: 5763 Cov.: 33 AF XY: 0.278 AC XY: 20683 AN XY: 74326

Gnomad4 AFR AF: 0.316

Gnomad4 AMR AF: 0.264

Gnomad4 ASJ AF: 0.209

Gnomad4 EAS AF: 0.315

Gnomad4 SAS AF: 0.312

Gnomad4 FIN AF: 0.266

Gnomad4 NFE AF: 0.253

Gnomad4 OTH AF: 0.269

Alfa AF: 0.256 Hom.: 5399

Bravo AF: 0.275

Asia WGS AF: 0.304 AC: 1062 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.4
DANN	Benign	0.47

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

LitVar

Other links and lift over

dbSNP: rs7768807; hg19: chr6-408246; COSMIC: COSV66705046; COSMIC: COSV66705046;