Genetic Variant IRF3:p.Gly337Arg (chr19-49660802-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001571.6(IRF3):c.1009G>A(p.Gly337Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000629 in 1,606,266 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000059 ( 1 hom. )

Consequence

IRF3
NM_001571.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.23

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 made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021212548).

BS2

High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF3	NM_001571.6 link	c.1009G>A	p.Gly337Arg	missense_variant	Exon 7 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.1009G>A	p.Gly337Arg	missense_variant	Exon 7 of 8	1	NM_001571.6	ENSP00000366344.3		Q14653-1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000115

AC:

AN:

235182

Hom.:

AF XY:

0.0000948

AC XY:

AN XY:

126648

show subpopulations

Gnomad AFR exome

AF:

0.000134

Gnomad AMR exome

AF:

0.000122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000171

Gnomad SAS exome

AF:

0.000107

Gnomad FIN exome

AF:

0.000244

Gnomad NFE exome

AF:

0.0000943

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000591

AC:

AN:

1454000

Hom.:

Cov.:

AF XY:

0.0000692

AC XY:

AN XY:

722312

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000691

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000760

Gnomad4 SAS exome

AF:

0.000142

Gnomad4 FIN exome

AF:

0.000587

Gnomad4 NFE exome

AF:

0.0000253

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000126

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

May 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

0.059

DANN

Benign

0.84

DEOGEN2

Benign

0.25

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

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.79

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

M_CAP

Benign

0.073

MetaRNN

Benign

0.021

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

MetaSVM

Benign

-0.48

MutationAssessor

Benign

-0.95

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

PROVEAN

Benign

-0.85

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

REVEL

Benign

0.26

Sift

Benign

0.67

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

Sift4G

Benign

0.86

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

Polyphen

0.012

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

Vest4

0.15

MutPred

0.71

.;Loss of glycosylation at S336 (P = 0.0394);Loss of glycosylation at S336 (P = 0.0394);Loss of glycosylation at S336 (P = 0.0394);.;.;.;.;.;.;.;

MVP

0.80

ClinPred

0.012

GERP RS

-9.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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