19-49662076-C-T

Variant names:

• chr19-49662076-C-T
• rs750526659
• NM_001571.6:c.854G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_001571.6(IRF3):​c.854G>A​(p.Arg285Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,613,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance,risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: IRF3 NM_001571.6 missense
• Clinical Significance: Uncertain significance; risk factor no assertion criteria provided U:1 O:1
• Conservation: PhyloP100: 3.94
• Publications: 10 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: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• BS2: High AC in GnomAdExome4 at 33 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001571.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF3	NM_001571.6	MANE Select	c.854G>A	p.Arg285Gln	missense	Exon 6 of 8	NP_001562.1	Q14653-1
	IRF3	NM_001197122.2		c.854G>A	p.Arg285Gln	missense	Exon 6 of 8	NP_001184051.1	Q14653-4
	IRF3	NM_001197123.2		c.749G>A	p.Arg250Gln	missense	Exon 6 of 8	NP_001184052.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF3	ENST00000377139.8	TSL:1 MANE Select	c.854G>A	p.Arg285Gln	missense	Exon 6 of 8	ENSP00000366344.3	Q14653-1
	IRF3	ENST00000601291.5	TSL:1	c.854G>A	p.Arg285Gln	missense	Exon 6 of 8	ENSP00000471896.1	Q14653-4
	IRF3	ENST00000309877.11	TSL:1	c.854G>A	p.Arg285Gln	missense	Exon 5 of 7	ENSP00000310127.6	Q14653-1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000399 AC: 10 AN: 250582 AF XY: 0.0000443

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000796

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461458 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 726996

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1111774

Other (OTH) AF: 0.0000497 AC: 3 AN: 60376

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74384

African (AFR) AF: 0.0000241 AC: 1 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.0000646 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000659 AC: 8

ClinVar

ClinVar submissions

Significance: Uncertain significance; risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	IRF3-related disorder (1)
-	-	-	Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		3.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.92		Loss of MoRF binding (P = 0.0291)
MVP		0.99
MPC		1.3
ClinPred		0.80	D
GERP RS		4.8
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.94
gMVP		0.94
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs750526659; hg19: chr19-50165333;