19-49659652-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001571.6(IRF3):​c.1280G>A​(p.Ser427Asn) 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. 13/18 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 Likely benign.

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

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.082167625).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF3	NM_001571.6	c.1280G>A	p.Ser427Asn	missense_variant	Exon 8 of 8	ENST00000377139.8	NP_001562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF3	ENST00000377139.8	c.1280G>A	p.Ser427Asn	missense_variant	Exon 8 of 8	1	NM_001571.6	ENSP00000366344.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	5.6
DANN	Benign	0.92
DEOGEN2	Benign	0.011	T;T;T;T;.;T;.;.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.55	T;.;.;T;T;.;.;T;.;.
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.082	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.014	D
MutationAssessor	Benign	0.0	.;N;N;N;.;.;.;.;.;.
PROVEAN	Benign	-0.50	.;N;N;.;.;.;.;.;.;.
REVEL	Benign	0.20
Sift	Benign	0.043	.;D;D;.;.;.;.;.;.;.
Sift4G	Uncertain	0.057	T;T;T;T;T;T;D;D;T;T
Polyphen		0.0	.;B;B;B;.;.;.;.;.;.
Vest4		0.072
MutPred		0.13		.;Loss of phosphorylation at S427 (P = 0.0241);Loss of phosphorylation at S427 (P = 0.0241);Loss of phosphorylation at S427 (P = 0.0241);.;.;.;.;.;.;
MVP		0.73
ClinPred		0.041	T
GERP RS		-1.1
Varity_R		0.13

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

Publications

LitVar

Other links and lift over

dbSNP: rs7251; hg19: chr19-50162909;