rs2230667

Variant names:

• chr19-49662445-C-T
• rs2230667
• NM_001571.6:c.581G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001571.6(IRF3):​c.581G>A​(p.Arg194Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000357 in 1,597,202 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000037 (1 hom.)
• Consequence: IRF3 NM_001571.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.68
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011281043).
• BS2: High AC in GnomAdExome4 at 54 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF3	NM_001571.6	c.581G>A	p.Arg194Gln	missense_variant	Exon 5 of 8	ENST00000377139.8	NP_001562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF3	ENST00000377139.8	c.581G>A	p.Arg194Gln	missense_variant	Exon 5 of 8	1	NM_001571.6	ENSP00000366344.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000581

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000101 AC: 23 AN: 227788 AF XY: 0.0000809

Gnomad AFR exome AF: 0.0000674

Gnomad AMR exome AF: 0.0000321

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000294

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000374 AC: 54 AN: 1444912 Hom.: 1 Cov.: 31 AF XY: 0.0000334 AC XY: 24 AN XY: 717836

African (AFR) AF: 0.0000305 AC: 1 AN: 32810

American (AMR) AF: 0.0000241 AC: 1 AN: 41574

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25160

East Asian (EAS) AF: 0.000511 AC: 20 AN: 39172

South Asian (SAS) AF: 0.00 AC: 0 AN: 84104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52678

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.0000254 AC: 28 AN: 1104226

Other (OTH) AF: 0.0000504 AC: 3 AN: 59498

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152290 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74470

African (AFR) AF: 0.00 AC: 0 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000582 AC: 3 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000682 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000660 AC: 8

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.048
DANN	Benign	0.65
DEOGEN2	Benign	0.0098	T;T;.;T;.;T;T;.;T;.;.;T;T;T;T;T;T;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0082	N
LIST_S2	Benign	0.79	T;.;T;T;T;.;T;T;.;.;T;.;.;T;T;T;T;T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.011	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.097	T
MutationAssessor	Benign	-0.17	.;N;.;.;N;N;N;N;.;.;.;.;.;.;.;.;.;.
PhyloP100		-1.7
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.71	.;N;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.17
Sift	Benign	0.79	.;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.62	T;T;T;D;T;T;T;T;T;T;T;T;T;.;T;.;.;.
Polyphen		0.0060	.;B;.;.;.;B;B;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.10
MutPred		0.31		.;Loss of methylation at K193 (P = 0.1403);Loss of methylation at K193 (P = 0.1403);.;Loss of methylation at K193 (P = 0.1403);Loss of methylation at K193 (P = 0.1403);Loss of methylation at K193 (P = 0.1403);Loss of methylation at K193 (P = 0.1403);.;.;.;.;.;Loss of methylation at K193 (P = 0.1403);Loss of methylation at K193 (P = 0.1403);.;.;.;
MVP		0.79
MPC		0.44
ClinPred		0.013	T
GERP RS		-8.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.077
gMVP		0.13
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs2230667; hg19: chr19-50165702;