Genetic Variant IRF4:c.745+144T>A (chr6-399079-T-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_002460.4(IRF4):c.745+144T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.754 in 469,018 control chromosomes in the GnomAD database, including 142,165 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.68 ( 39508 hom., cov: 32)

Exomes 𝑓: 0.79 ( 102657 hom. )

Consequence

IRF4
NM_002460.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.51

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 6-399079-T-A is Benign according to our data. Variant chr6-399079-T-A is described in ClinVar as [Benign]. Clinvar id is 1268521.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.862 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF4	NM_002460.4 link	c.745+144T>A		intron_variant	Intron 6 of 8	ENST00000380956.9	NP_002451.2	Q15306-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
IRF4	ENST00000380956.9 link	c.745+144T>A	intron_variant	Intron 6 of 8	1	NM_002460.4	ENSP00000370343.4	Q15306-1
IRF4	ENST00000696871.1 link	c.742+144T>A	intron_variant	Intron 6 of 8			ENSP00000512940.1	Q15306-2
IRF4	ENST00000696873.1 link	c.310+144T>A	intron_variant	Intron 5 of 5			ENSP00000512942.1	A0A8Q3WLQ3
IRF4	ENST00000493114.2 link	n.742+144T>A	intron_variant	Intron 6 of 9	5		ENSP00000436094.2	F2Z3D5

Frequencies

GnomAD3 genomes

AF:

0.679

AC:

103152

AN:

151982

Hom.:

39521

Cov.:

show subpopulations

Gnomad AFR

AF:

0.313

Gnomad AMI

AF:

0.741

Gnomad AMR

AF:

0.706

Gnomad ASJ

AF:

0.851

Gnomad EAS

AF:

0.483

Gnomad SAS

AF:

0.715

Gnomad FIN

AF:

0.867

Gnomad MID

AF:

0.731

Gnomad NFE

AF:

0.868

Gnomad OTH

AF:

0.686

GnomAD4 exome

AF:

0.790

AC:

250372

AN:

316918

Hom.:

102657

AF XY:

0.794

AC XY:

129415

AN XY:

162998

show subpopulations

Gnomad4 AFR exome

AF:

0.306

Gnomad4 AMR exome

AF:

0.713

Gnomad4 ASJ exome

AF:

0.851

Gnomad4 EAS exome

AF:

0.484

Gnomad4 SAS exome

AF:

0.704

Gnomad4 FIN exome

AF:

0.861

Gnomad4 NFE exome

AF:

0.864

Gnomad4 OTH exome

AF:

0.765

GnomAD4 genome

AF:

0.678

AC:

103134

AN:

152100

Hom.:

39508

Cov.:

AF XY:

0.676

AC XY:

50289

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.313

Gnomad4 AMR

AF:

0.705

Gnomad4 ASJ

AF:

0.851

Gnomad4 EAS

AF:

0.482

Gnomad4 SAS

AF:

0.715

Gnomad4 FIN

AF:

0.867

Gnomad4 NFE

AF:

0.868

Gnomad4 OTH

AF:

0.684

Alfa

AF:

0.768

Hom.:

6040

Bravo

AF:

0.649

Asia WGS

AF:

0.568

AC:

1976

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

-0.90

CADD

Benign

0.19

DANN

Benign

0.50

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over