rs779357935

Variant names:

• chr19-49659612-C-A
• rs779357935
• ENST00000601291.5:c.1336G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-49659612-C-A
• chr19-49659612-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001197122.2(IRF3):​c.1336G>T​(p.Val446Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,435,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V446I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: IRF3 NM_001197122.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.65
• Publications: 0 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12301767).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001197122.2. 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.*36G>T		3_prime_UTR	Exon 8 of 8	NP_001562.1	Q14653-1
	IRF3	NM_001197122.2		c.1336G>T	p.Val446Phe	missense	Exon 8 of 8	NP_001184051.1	Q14653-4
	IRF3	NM_001197123.2		c.*36G>T		3_prime_UTR	Exon 8 of 8	NP_001184052.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF3	ENST00000601291.5	TSL:1	c.1336G>T	p.Val446Phe	missense	Exon 8 of 8	ENSP00000471896.1	Q14653-4
	IRF3	ENST00000377139.8	TSL:1 MANE Select	c.*36G>T		3_prime_UTR	Exon 8 of 8	ENSP00000366344.3	Q14653-1
	IRF3	ENST00000309877.11	TSL:1	c.*36G>T		3_prime_UTR	Exon 7 of 7	ENSP00000310127.6	Q14653-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1435826 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 712196

African (AFR) AF: 0.00 AC: 0 AN: 32780

American (AMR) AF: 0.00 AC: 0 AN: 39636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25474

East Asian (EAS) AF: 0.00 AC: 0 AN: 38188

South Asian (SAS) AF: 0.00 AC: 0 AN: 83372

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51832

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099354

Other (OTH) AF: 0.0000168 AC: 1 AN: 59470

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	0.088
DANN	Benign	0.49
DEOGEN2	Benign	0.028	T
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.12	T
PhyloP100		-2.7
PrimateAI	Benign	0.28	T
Vest4		0.14
MVP		0.87
MPC		0.83
GERP RS		-4.0
gMVP		0.25
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs779357935; hg19: chr19-50162869;