rs968457

Positions:

chr19-49663393-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001571.6(IRF3):c.287G>A(p.Arg96Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00346 in 1,614,152 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R96W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.018 ( 77 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 74 hom. )

Consequence

IRF3
NM_001571.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.707

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035091639).

BP6

Variant 19-49663393-C-T is Benign according to our data. Variant chr19-49663393-C-T is described in ClinVar as [Benign]. Clinvar id is 778853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF3	NM_001571.6 linkuse as main transcript	c.287G>A	p.Arg96Gln	missense_variant	3/8	ENST00000377139.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF3	ENST00000377139.8 linkuse as main transcript	c.287G>A	p.Arg96Gln	missense_variant	3/8	1	NM_001571.6	P1	Q14653-1

Frequencies

GnomAD3 genomes

AF:

0.0180

AC:

2737

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0615

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00786

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.0172

GnomAD3 exomes

AF:

0.00504

AC:

1268

AN:

251448

Hom.:

AF XY:

0.00355

AC XY:

483

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0669

Gnomad AMR exome

AF:

0.00362

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00195

AC:

2845

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

1178

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0624

Gnomad4 AMR exome

AF:

0.00429

Gnomad4 ASJ exome

AF:

0.00119

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000186

Gnomad4 OTH exome

AF:

0.00470

GnomAD4 genome

AF:

0.0180

AC:

2738

AN:

152270

Hom.:

Cov.:

AF XY:

0.0172

AC XY:

1281

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0613

Gnomad4 AMR

AF:

0.00785

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.0170

Alfa

AF:

0.00350

Hom.:

Bravo

AF:

0.0207

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0570

AC:

251

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00616

AC:

748

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 31, 2018	- -

IRF3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2019

This variant is classified as 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

0.079

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.58

D;.;.;D;D;.;T;T;T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.76

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

MetaRNN

Benign

0.0035

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

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.4

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

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.87

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

REVEL

Benign

0.23

Sift

Benign

0.30

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

Sift4G

Benign

0.31

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

Polyphen

0.20

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

Vest4

0.12

MVP

0.92

MPC

0.46

ClinPred

0.0082

GERP RS

-3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.18

gMVP

0.25

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