19-49659652-C-A

Variant names:

• chr19-49659652-C-A
• rs7251
• NM_001571.6:c.1280G>T

Variant summary

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

The NM_001571.6(IRF3):​c.1280G>T​(p.Ser427Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/18 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. S427T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: IRF3 NM_001571.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.636
• Publications: 88 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=0.07384366).

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.1280G>T	p.Ser427Ile	missense	Exon 8 of 8	NP_001562.1	Q14653-1
	IRF3	NM_001197122.2		c.1296G>T	p.Glu432Asp	missense	Exon 8 of 8	NP_001184051.1	Q14653-4
	IRF3	NM_001197123.2		c.1175G>T	p.Ser392Ile	missense	Exon 8 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.1280G>T	p.Ser427Ile	missense	Exon 8 of 8	ENSP00000366344.3	Q14653-1
	IRF3	ENST00000601291.5	TSL:1	c.1296G>T	p.Glu432Asp	missense	Exon 8 of 8	ENSP00000471896.1	Q14653-4
	IRF3	ENST00000309877.11	TSL:1	c.1280G>T	p.Ser427Ile	missense	Exon 7 of 7	ENSP00000310127.6	Q14653-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 3182

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Uncertain	0.050
CADD	Benign	7.4
DANN	Benign	0.92
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.074	T
PhyloP100		-0.64
PrimateAI	Benign	0.26	T
Vest4		0.041
MVP		0.91
MPC		0.48
ClinPred		0.044	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.060
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: rs7251; hg19: chr19-50162909;