19-49665683-A-G

Variant names:

• chr19-49665683-A-G
• rs3204440
• NM_001571.6:c.-61T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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=-0.42).
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0669 is higher than 0.05.

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.-61T>C		5_prime_UTR	Exon 1 of 8	NP_001562.1	Q14653-1
	IRF3	NM_001197122.2		c.-61T>C		5_prime_UTR	Exon 1 of 8	NP_001184051.1	Q14653-4
	IRF3	NM_001197123.2		c.-224T>C		5_prime_UTR	Exon 1 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.-61T>C		5_prime_UTR	Exon 1 of 8	ENSP00000366344.3	Q14653-1
	IRF3	ENST00000601291.5	TSL:1	c.-61T>C		5_prime_UTR	Exon 1 of 8	ENSP00000471896.1	Q14653-4
	IRF3	ENST00000599223.5	TSL:1	c.-61T>C		5_prime_UTR	Exon 1 of 7	ENSP00000471358.1	Q14653-2

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

African (AFR) AF: 0.0453 AC: 1058 AN: 23358

American (AMR) AF: 0.0373 AC: 932 AN: 24984

Ashkenazi Jewish (ASJ) AF: 0.0454 AC: 793 AN: 17466

East Asian (EAS) AF: 0.0180 AC: 658 AN: 36496

South Asian (SAS) AF: 0.0317 AC: 1881 AN: 59356

European-Finnish (FIN) AF: 0.0227 AC: 775 AN: 34074

Middle Eastern (MID) AF: 0.0750 AC: 222 AN: 2960

European-Non Finnish (NFE) AF: 0.0486 AC: 37801 AN: 777440

Other (OTH) AF: 0.0506 AC: 2255 AN: 44550

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

African (AFR) AF: 0.0424 AC: 1760 AN: 41488

American (AMR) AF: 0.0481 AC: 735 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0412 AC: 143 AN: 3470

East Asian (EAS) AF: 0.0180 AC: 93 AN: 5166

South Asian (SAS) AF: 0.0317 AC: 153 AN: 4826

European-Finnish (FIN) AF: 0.0189 AC: 200 AN: 10596

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0479 AC: 3254 AN: 67998

Other (OTH) AF: 0.0412 AC: 87 AN: 2110

Alfa AF: 0.0423 Hom.: 184

Bravo AF: 0.0449

Asia WGS AF: 0.0350 AC: 120 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	4.9
DANN	Benign	0.65
PhyloP100		0.047
PromoterAI		0.0078	Neutral
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs3204440; hg19: chr19-50168940;