Variant 4-184408164-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002199.4(IRF2):c.523A>T(p.Ile175Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000707 in 1,579,188 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00038 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 1 hom. )

Consequence

IRF2
NM_002199.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.75

Variant links:

Genes affected

IRF2 (HGNC:6117): (interferon regulatory factor 2) IRF2 encodes interferon regulatory factor 2, a member of the interferon regulatory transcription factor (IRF) family. IRF2 competitively inhibits the IRF1-mediated transcriptional activation of interferons alpha and beta, and presumably other genes that employ IRF1 for transcription activation. However, IRF2 also functions as a transcriptional activator of histone H4. [provided by RefSeq, Jul 2008]

IRF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06925094).

BS2

High AC in GnomAd4 at 58 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF2	NM_002199.4 linkuse as main transcript	c.523A>T	p.Ile175Phe	missense_variant	6/9	ENST00000393593.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF2	ENST00000393593.8 linkuse as main transcript	c.523A>T	p.Ile175Phe	missense_variant	6/9	1	NM_002199.4	P1	P14316-1

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000283

AC:

AN:

250498

Hom.:

AF XY:

0.000296

AC XY:

AN XY:

135318

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000538

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000742

AC:

1059

AN:

1426876

Hom.:

Cov.:

AF XY:

0.000708

AC XY:

504

AN XY:

712216

show subpopulations

Gnomad4 AFR exome

AF:

0.0000611

Gnomad4 AMR exome

AF:

0.000180

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000949

Gnomad4 OTH exome

AF:

0.000405

GnomAD4 genome

AF:

0.000381

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000735

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000527

Hom.:

Bravo

AF:

0.000321

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000296

AC:

EpiCase

AF:

0.000819

EpiControl

AF:

0.000712

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2022

The c.523A>T (p.I175F) alteration is located in exon 6 (coding exon 5) of the IRF2 gene. This alteration results from a A to T substitution at nucleotide position 523, causing the isoleucine (I) at amino acid position 175 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Uncertain

0.020

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.20

T;.

Eigen

Benign

-0.17

Eigen_PC

Benign

0.019

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.78

T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.069

T;T

MetaSVM

Uncertain

0.63

MutationAssessor

Benign

1.9

L;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.89

N;N

REVEL

Uncertain

0.38

Sift

Benign

0.62

T;T

Sift4G

Benign

0.56

T;.

Polyphen

0.0010

B;.

Vest4

0.29

MVP

0.92

MPC

1.3

ClinPred

0.025

GERP RS

5.3

Varity_R

0.065

gMVP

0.32

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