rs2671422

chr6-398775-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002460.4(IRF4):c.638-53G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,345,942 control chromosomes in the GnomAD database, including 22,107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4668 hom., cov: 33)
  • Exomes 𝑓: 0.14 (17439 hom.)
• Consequence: IRF4 NM_002460.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.28

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-398775-G-A is Benign according to our data. Variant chr6-398775-G-A is described in ClinVar as [Benign]. Clinvar id is 1273865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF4	NM_002460.4	c.638-53G>A		intron_variant		ENST00000380956.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF4	ENST00000380956.9	c.638-53G>A		intron_variant		1	NM_002460.4	P4
IRF4	ENST00000696871.1	c.635-53G>A		intron_variant				A1
IRF4	ENST00000696873.1	c.203-53G>A		intron_variant
IRF4	ENST00000493114.2	c.635-53G>A		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32363 AN: 152046 Hom.: 4631 Cov.: 33

Gnomad AFR AF: 0.349

Gnomad AMI AF: 0.245

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.516

Gnomad SAS AF: 0.271

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.223

GnomAD4 exome AF: 0.145 AC: 172771 AN: 1193778 Hom.: 17439 AF XY: 0.146 AC XY: 87451 AN XY: 597336

Gnomad4 AFR exome AF: 0.350

Gnomad4 AMR exome AF: 0.250

Gnomad4 ASJ exome AF: 0.123

Gnomad4 EAS exome AF: 0.513

Gnomad4 SAS exome AF: 0.253

Gnomad4 FIN exome AF: 0.124

Gnomad4 NFE exome AF: 0.109

Gnomad4 OTH exome AF: 0.165

GnomAD4 genome AF: 0.213 AC: 32467 AN: 152164 Hom.: 4668 Cov.: 33 AF XY: 0.217 AC XY: 16149 AN XY: 74402

Gnomad4 AFR AF: 0.350

Gnomad4 AMR AF: 0.242

Gnomad4 ASJ AF: 0.127

Gnomad4 EAS AF: 0.517

Gnomad4 SAS AF: 0.271

Gnomad4 FIN AF: 0.121

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.225

Alfa AF: 0.137 Hom.: 3532

Bravo AF: 0.228

Asia WGS AF: 0.406 AC: 1410 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 51% of patients studied by a panel of primary immunodeficiencies. Number of patients: 48. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.023
Dann	Benign	0.53

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: rs2671422; hg19: chr6-398775; COSMIC: COSV66706678; COSMIC: COSV66706678;