rs3204440

chr19-49665683-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001571.6(IRF3):c.-61T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0451 in 1,172,822 control chromosomes in the GnomAD database, including 1,317 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.043 (138 hom., cov: 33)
  • Exomes 𝑓: 0.045 (1179 hom.)
• Consequence: IRF3 NM_001571.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0470

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

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0669 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF3	NM_001571.6	c.-61T>C		5_prime_UTR_variant	1/8	ENST00000377139.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF3	ENST00000377139.8	c.-61T>C		5_prime_UTR_variant	1/8	1	NM_001571.6	P1

Frequencies

GnomAD3 genomes AF: 0.0429 AC: 6521 AN: 152020 Hom.: 138 Cov.: 33

Gnomad AFR AF: 0.0425

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.0482

Gnomad ASJ AF: 0.0412

Gnomad EAS AF: 0.0180

Gnomad SAS AF: 0.0319

Gnomad FIN AF: 0.0189

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0478

Gnomad OTH AF: 0.0417

GnomAD4 exome AF: 0.0454 AC: 46375 AN: 1020684 Hom.: 1179 Cov.: 13 AF XY: 0.0453 AC XY: 22977 AN XY: 507708

Gnomad4 AFR exome AF: 0.0453

Gnomad4 AMR exome AF: 0.0373

Gnomad4 ASJ exome AF: 0.0454

Gnomad4 EAS exome AF: 0.0180

Gnomad4 SAS exome AF: 0.0317

Gnomad4 FIN exome AF: 0.0227

Gnomad4 NFE exome AF: 0.0486

Gnomad4 OTH exome AF: 0.0506

GnomAD4 genome AF: 0.0429 AC: 6523 AN: 152138 Hom.: 138 Cov.: 33 AF XY: 0.0409 AC XY: 3040 AN XY: 74370

Gnomad4 AFR AF: 0.0424

Gnomad4 AMR AF: 0.0481

Gnomad4 ASJ AF: 0.0412

Gnomad4 EAS AF: 0.0180

Gnomad4 SAS AF: 0.0317

Gnomad4 FIN AF: 0.0189

Gnomad4 NFE AF: 0.0479

Gnomad4 OTH AF: 0.0412

Alfa AF: 0.0394 Hom.: 16

Bravo AF: 0.0449

Asia WGS AF: 0.0350 AC: 120 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	4.9
Dann	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs3204440; hg19: chr19-50168940;