19-49665670-A-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001571.6(IRF3):​c.-48T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000068 in 882,752 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: IRF3 NM_001571.6 5_prime_UTR
• Scores: Splicing: ADA: 0.0002698
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000680 AC: 6 AN: 882752 Hom.: 0 Cov.: 12 AF XY: 0.00000904 AC XY: 4 AN XY: 442500

African (AFR) AF: 0.0000485 AC: 1 AN: 20620

American (AMR) AF: 0.0000445 AC: 1 AN: 22486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16426

East Asian (EAS) AF: 0.00 AC: 0 AN: 35440

South Asian (SAS) AF: 0.00 AC: 0 AN: 55950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2708

European-Non Finnish (NFE) AF: 0.00000609 AC: 4 AN: 656576

Other (OTH) AF: 0.00 AC: 0 AN: 40070

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.9
DANN	Benign	0.72
PhyloP100		-0.64
PromoterAI		0.024	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00027
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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;