19-49659723-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000601291.5(IRF3):c.1225C>T(p.His409Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,613,928 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0077 (13 hom., cov: 31)
  • Exomes 𝑓: 0.00073 (14 hom.)
• Consequence: IRF3 ENST00000601291.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.499

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004697025).
• BP6: Variant 19-49659723-G-A is Benign according to our data. Variant chr19-49659723-G-A is described in ClinVar as [Benign]. Clinvar id is 3039781.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00766 (1166/152188) while in subpopulation AFR AF= 0.0269 (1116/41498). AF 95% confidence interval is 0.0256. There are 13 homozygotes in gnomad4. There are 543 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 1164 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF3	NM_001571.6	c.1209C>T	p.Leu403=	synonymous_variant	8/8	ENST00000377139.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF3	ENST00000377139.8	c.1209C>T	p.Leu403=	synonymous_variant	8/8	1	NM_001571.6	P1

Frequencies

GnomAD3 genomes AF: 0.00765 AC: 1164 AN: 152070 Hom.: 13 Cov.: 31

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00196 AC: 492 AN: 251146 Hom.: 7 AF XY: 0.00147 AC XY: 200 AN XY: 135732

Gnomad AFR exome AF: 0.0269

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000732 AC: 1070 AN: 1461740 Hom.: 14 Cov.: 33 AF XY: 0.000615 AC XY: 447 AN XY: 727184

Gnomad4 AFR exome AF: 0.0270

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.00766 AC: 1166 AN: 152188 Hom.: 13 Cov.: 31 AF XY: 0.00730 AC XY: 543 AN XY: 74412

Gnomad4 AFR AF: 0.0269

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00142 Hom.: 1

Bravo AF: 0.00898

ESP6500AA AF: 0.0236 AC: 104

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00251 AC: 305

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

IRF3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 29, 2024

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
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	5.7
Dann	Benign	0.85
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.45	T;T;T
MetaRNN	Benign	0.0047	T;T;T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.35	T
Sift4G	Benign	0.16	T;D;D
Vest4		0.47
MVP		0.94
MPC		0.55
GERP RS		0.55
gMVP		0.36

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: rs11554833; hg19: chr19-50162980;