19-49665670-A-C

Variant names:

• chr19-49665670-A-C
• rs2304205
• NM_001571.6:c.-48T>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001571.6(IRF3):​c.-48T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,031,916 control chromosomes in the GnomAD database, including 42,351 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 0.36 (11519 hom., cov: 32)
  • Exomes 𝑓: 0.26 (30832 hom.)
• Consequence: IRF3 NM_001571.6 5_prime_UTR
• Scores: Splicing: ADA: 0.0001454
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.644
• Publications: 28 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.6 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF3	NM_001571.6	c.-48T>G		5_prime_UTR_variant	Exon 1 of 8	ENST00000377139.8	NP_001562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF3	ENST00000377139.8	c.-48T>G		5_prime_UTR_variant	Exon 1 of 8	1	NM_001571.6	ENSP00000366344.3

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54243 AN: 151442 Hom.: 11485 Cov.: 32

Gnomad AFR AF: 0.606

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.321

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.225

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.323

GnomAD4 exome AF: 0.256 AC: 225605 AN: 880358 Hom.: 30832 Cov.: 12 AF XY: 0.258 AC XY: 113748 AN XY: 441416

African (AFR) AF: 0.610 AC: 12539 AN: 20572

American (AMR) AF: 0.302 AC: 6787 AN: 22452

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 3948 AN: 16396

East Asian (EAS) AF: 0.187 AC: 6630 AN: 35392

South Asian (SAS) AF: 0.313 AC: 17507 AN: 55844

European-Finnish (FIN) AF: 0.226 AC: 7337 AN: 32420

Middle Eastern (MID) AF: 0.384 AC: 1036 AN: 2700

European-Non Finnish (NFE) AF: 0.243 AC: 158839 AN: 654588

Other (OTH) AF: 0.275 AC: 10982 AN: 39994

GnomAD4 genome AF: 0.358 AC: 54330 AN: 151558 Hom.: 11519 Cov.: 32 AF XY: 0.353 AC XY: 26115 AN XY: 74066

African (AFR) AF: 0.606 AC: 25006 AN: 41262

American (AMR) AF: 0.320 AC: 4878 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 824 AN: 3458

East Asian (EAS) AF: 0.189 AC: 971 AN: 5132

South Asian (SAS) AF: 0.310 AC: 1488 AN: 4800

European-Finnish (FIN) AF: 0.225 AC: 2362 AN: 10506

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.260 AC: 17670 AN: 67856

Other (OTH) AF: 0.325 AC: 686 AN: 2114

Alfa AF: 0.266 Hom.: 2838

Bravo AF: 0.374

Asia WGS AF: 0.346 AC: 1198 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	10
DANN	Benign	0.63
PhyloP100		-0.64
PromoterAI		0.038	Neutral
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.040		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: rs2304205; hg19: chr19-50168927; COSMIC: COSV55864079; COSMIC: COSV55864079;