rs968457

chr19-49663393-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.707

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]

ACMG classification

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	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	c.287G>A	p.Arg96Gln	missense_variant	3/8	1	NM_001571.6	P1

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2737 AN: 152152 Hom.: 77 Cov.: 33

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.: 29 AF XY: 0.00355 AC XY: 483 AN XY: 135902

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.: 74 Cov.: 32 AF XY: 0.00162 AC XY: 1178 AN XY: 727244

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.: 77 Cov.: 33 AF XY: 0.0172 AC XY: 1281 AN XY: 74450

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.: 25

Bravo AF: 0.0207

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0570 AC: 251

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00616 AC: 748

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

IRF3-related disorder Benign:1

Benign, criteria provided, single submitter

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	14
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	N
MetaRNN	Benign	0.0035	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.4	M;.;M;M;M;M;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.22	T
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	T
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

Other links and lift over

dbSNP: rs968457; hg19: chr19-50166650; COSMIC: COSV104370580; COSMIC: COSV104370580;