rs143769046

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001571.6(IRF3):c.829G>A(p.Ala277Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00605 in 1,613,680 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0044 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0062 ( 39 hom. )

Consequence

IRF3
NM_001571.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4O:1

Conservation

PhyloP100: -0.533

Publications

12 publications found

Variant links:

Genes affected

IRF3 (HGNC:6118): (interferon regulatory factor 3) This gene encodes a member of the interferon regulatory transcription factor (IRF) family. The encoded protein is found in an inactive cytoplasmic form that upon serine/threonine phosphorylation forms a complex with CREBBP. This complex translocates to the nucleus and activates the transcription of interferons alpha and beta, as well as other interferon-induced genes. The protein plays an important role in the innate immune response against DNA and RNA viruses. Mutations in this gene are associated with Encephalopathy, acute, infection-induced, herpes-specific, 7. [provided by RefSeq, Sep 2020]

IRF3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011467636).

BP6

Variant 19-49662101-C-T is Benign according to our data. Variant chr19-49662101-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 495307.

BS2

High AC in GnomAd4 at 671 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF3	NM_001571.6 link	c.829G>A	p.Ala277Thr	missense_variant	Exon 6 of 8	ENST00000377139.8	NP_001562.1	Q14653-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF3	ENST00000377139.8 link	c.829G>A	p.Ala277Thr	missense_variant	Exon 6 of 8	1	NM_001571.6	ENSP00000366344.3		Q14653-1

Frequencies

GnomAD3 genomes

AF:

0.00441

AC:

671

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.0538

Gnomad AMR

AF:

0.00602

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00245

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00650

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00394

AC:

988

AN:

250464

AF XY:

0.00385

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00420

Gnomad ASJ exome

AF:

0.000597

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00283

Gnomad NFE exome

AF:

0.00615

Gnomad OTH exome

AF:

0.00490

GnomAD4 exome

AF:

0.00622

AC:

9088

AN:

1461312

Hom.:

Cov.:

AF XY:

0.00607

AC XY:

4409

AN XY:

726898

show subpopulations

African (AFR)

AF:

0.000687

AC:

AN:

33472

American (AMR)

AF:

0.00515

AC:

230

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.000421

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00136

AC:

117

AN:

86242

European-Finnish (FIN)

AF:

0.00304

AC:

162

AN:

53282

Middle Eastern (MID)

AF:

0.00503

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00742

AC:

8244

AN:

1111684

Other (OTH)

AF:

0.00451

AC:

272

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

557

1114

1671

2228

2785

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

324

648

972

1296

1620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00440

AC:

671

AN:

152368

Hom.:

Cov.:

AF XY:

0.00434

AC XY:

323

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

41584

American (AMR)

AF:

0.00601

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000827

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00245

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00650

AC:

442

AN:

68034

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

117

156

195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00451

Hom.:

Bravo

AF:

0.00467

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00640

AC:

ExAC

AF:

0.00362

AC:

439

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00567

EpiControl

AF:

0.00646

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

IRF3: BS1 -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 7

Uncertain:1Other:1

Mar 14, 2018

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 25, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

IRF3-related disorder

Benign:1

Mar 16, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Benign

5.8

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.30

T;T;.;.;T;T;T;T;T;T

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.84

T;.;T;T;.;T;.;.;.;T

M_CAP

Benign

0.084

MetaRNN

Benign

0.011

T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.21

MutationAssessor

Uncertain

2.2

.;M;.;M;M;M;.;.;.;.

PhyloP100

-0.53

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.54

.;N;.;.;N;.;.;.;.;.

REVEL

Uncertain

0.36

Sift

Benign

0.34

.;T;.;.;T;.;.;.;.;.

Sift4G

Benign

0.13

T;T;T;T;T;T;T;T;T;T

Polyphen

0.21

.;B;.;.;B;B;.;.;.;.

Vest4

0.14

MVP

0.95

MPC

0.54

ClinPred

0.0089

GERP RS

-0.52

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.0

Varity_R

0.14

gMVP

0.27

Mutation Taster

=81/19

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over