rs2304207

Variant names:

• chr19-49664469-C-G
• rs2304207
• ENST00000593922.5:c.-300G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-49664469-C-G
• chr19-49664469-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001197123.2(IRF3):​c.34G>C​(p.Val12Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,530,516 control chromosomes in the GnomAD database, including 19,015 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 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 0.14 (1609 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17406 hom.)
• Consequence: IRF3 NM_001197123.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.166
• Publications: 24 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]

BCL2L12 (HGNC:13787): (BCL2 like 12) This gene encodes a member of a family of proteins containing a Bcl-2 homology domain 2 (BH2). The encoded protein is an anti-apoptotic factor that acts as an inhibitor of caspases 3 and 7 in the cytoplasm. In the nucleus, it binds to the p53 tumor suppressor protein, preventing its association with target genes. Overexpression of this gene has been detected in a number of different cancers. There is a pseudogene for this gene on chromosome 3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001197123.2. 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.165+205G>C		intron	N/A	NP_001562.1	Q14653-1
	IRF3	NM_001197123.2		c.34G>C	p.Val12Leu	missense	Exon 2 of 8	NP_001184052.1
	IRF3	NM_001197122.2		c.165+205G>C		intron	N/A	NP_001184051.1	Q14653-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF3	ENST00000593922.5	TSL:1	c.-300G>C		5_prime_UTR	Exon 2 of 8	ENSP00000472601.1	M0QYT9
	IRF3	ENST00000377139.8	TSL:1 MANE Select	c.165+205G>C		intron	N/A	ENSP00000366344.3	Q14653-1
	IRF3	ENST00000601291.5	TSL:1	c.165+205G>C		intron	N/A	ENSP00000471896.1	Q14653-4

Frequencies

GnomAD3 genomes AF: 0.138 AC: 21032 AN: 151926 Hom.: 1608 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.0226

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.128

GnomAD2 exomes AF: 0.139 AC: 20200 AN: 144962 AF XY: 0.147

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.0755

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.0225

Gnomad FIN exome AF: 0.163

Gnomad NFE exome AF: 0.161

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.154 AC: 212044 AN: 1378472 Hom.: 17406 Cov.: 31 AF XY: 0.156 AC XY: 106510 AN XY: 681046

African (AFR) AF: 0.112 AC: 3528 AN: 31510

American (AMR) AF: 0.0806 AC: 2865 AN: 35542

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 3889 AN: 24880

East Asian (EAS) AF: 0.0196 AC: 691 AN: 35190

South Asian (SAS) AF: 0.206 AC: 16393 AN: 79750

European-Finnish (FIN) AF: 0.154 AC: 5154 AN: 33398

Middle Eastern (MID) AF: 0.248 AC: 1399 AN: 5636

European-Non Finnish (NFE) AF: 0.157 AC: 169246 AN: 1075146

Other (OTH) AF: 0.155 AC: 8879 AN: 57420

GnomAD4 genome AF: 0.138 AC: 21041 AN: 152044 Hom.: 1609 Cov.: 32 AF XY: 0.137 AC XY: 10174 AN XY: 74280

African (AFR) AF: 0.109 AC: 4537 AN: 41486

American (AMR) AF: 0.107 AC: 1629 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 519 AN: 3470

East Asian (EAS) AF: 0.0226 AC: 117 AN: 5170

South Asian (SAS) AF: 0.199 AC: 959 AN: 4810

European-Finnish (FIN) AF: 0.163 AC: 1721 AN: 10550

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.163 AC: 11105 AN: 67960

Other (OTH) AF: 0.128 AC: 270 AN: 2108

Alfa AF: 0.139 Hom.: 1014

Bravo AF: 0.130

Asia WGS AF: 0.128 AC: 445 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.5
DANN	Benign	0.40
PhyloP100		-0.17
PromoterAI		0.094	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs2304207; hg19: chr19-50167726; COSMIC: COSV55862786; COSMIC: COSV55862786;