rs143769046

Positions:

chr19-49662101-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0044 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0062 ( 39 hom. )

Consequence

IRF3
NM_001571.6 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: -0.533

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:

IRF3 (HGNC:):

IRF3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 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 [Likely_benign]. Clinvar id is 495307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49662101-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 671 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRF3	NM_001571.6 linkuse as main transcript	c.829G>A	p.Ala277Thr	missense_variant	6/8	ENST00000377139.8	NP_001562.1	Q14653-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRF3	ENST00000377139.8 linkuse as main transcript	c.829G>A	p.Ala277Thr	missense_variant	6/8	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

GnomAD3 exomes

AF:

0.00394

AC:

988

AN:

250464

Hom.:

AF XY:

0.00385

AC XY:

521

AN XY:

135468

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 SAS exome

AF:

0.00111

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

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.00515

Gnomad4 ASJ exome

AF:

0.000421

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00136

Gnomad4 FIN exome

AF:

0.00304

Gnomad4 NFE exome

AF:

0.00742

Gnomad4 OTH exome

AF:

0.00451

GnomAD4 genome

AF:

0.00440

AC:

671

AN:

152368

Hom.:

Cov.:

AF XY:

0.00434

AC XY:

323

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.00601

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000827

Gnomad4 FIN

AF:

0.00245

Gnomad4 NFE

AF:

0.00650

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00513

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: Likely benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	IRF3: BS1 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

IRF3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 16, 2020

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). -

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

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Mar 14, 2018

- -

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

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;.;.;.;.

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

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