rs2671422

Variant names:

• chr6-398775-G-A
• rs2671422
• NM_002460.4:c.638-53G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-398775-G-A
• chr6-398775-G-C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 19 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]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
IRF4	NM_002460.4	c.638-53G>A		intron_variant	Intron 5 of 8	ENST00000380956.9	NP_002451.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF4	ENST00000380956.9	c.638-53G>A		intron_variant	Intron 5 of 8	1	NM_002460.4	ENSP00000370343.4
IRF4	ENST00000696871.1	c.635-53G>A		intron_variant	Intron 5 of 8			ENSP00000512940.1
IRF4	ENST00000696873.1	c.203-53G>A		intron_variant	Intron 4 of 5			ENSP00000512942.1
IRF4	ENST00000493114.2	n.635-53G>A		intron_variant	Intron 5 of 9	5		ENSP00000436094.2

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

African (AFR) AF: 0.350 AC: 9784 AN: 27936

American (AMR) AF: 0.250 AC: 10226 AN: 40846

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 2808 AN: 22922

East Asian (EAS) AF: 0.513 AC: 19093 AN: 37224

South Asian (SAS) AF: 0.253 AC: 19087 AN: 75442

European-Finnish (FIN) AF: 0.124 AC: 6296 AN: 50812

Middle Eastern (MID) AF: 0.171 AC: 824 AN: 4818

European-Non Finnish (NFE) AF: 0.109 AC: 96300 AN: 883292

Other (OTH) AF: 0.165 AC: 8353 AN: 50486

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

African (AFR) AF: 0.350 AC: 14522 AN: 41500

American (AMR) AF: 0.242 AC: 3703 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 441 AN: 3470

East Asian (EAS) AF: 0.517 AC: 2675 AN: 5170

South Asian (SAS) AF: 0.271 AC: 1305 AN: 4818

European-Finnish (FIN) AF: 0.121 AC: 1287 AN: 10598

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7778 AN: 67996

Other (OTH) AF: 0.225 AC: 476 AN: 2112

Alfa AF: 0.149 Hom.: 9384

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

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.023
DANN	Benign	0.53
PhyloP100		-2.3
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: rs2671422; hg19: chr6-398775; COSMIC: COSV66706678; COSMIC: COSV66706678;