chr19-49664697-G-C

Variant names:

• chr19-49664697-G-C
• rs76863988
• NM_001571.6:c.142C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001571.6(IRF3):​c.142C>G​(p.Gln48Glu) 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. 16/22 in silico tools predict 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)
• Consequence: IRF3 NM_001571.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0140
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050522864).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF3	NM_001571.6	MANE Select	c.142C>G	p.Gln48Glu	missense	Exon 2 of 8	NP_001562.1
	IRF3	NM_001197122.2		c.142C>G	p.Gln48Glu	missense	Exon 2 of 8	NP_001184051.1
	IRF3	NM_001197124.2		c.142C>G	p.Gln48Glu	missense	Exon 2 of 7	NP_001184053.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF3	ENST00000377139.8	TSL:1 MANE Select	c.142C>G	p.Gln48Glu	missense	Exon 2 of 8	ENSP00000366344.3
	IRF3	ENST00000601291.5	TSL:1	c.142C>G	p.Gln48Glu	missense	Exon 2 of 8	ENSP00000471896.1
	IRF3	ENST00000309877.11	TSL:1	c.142C>G	p.Gln48Glu	missense	Exon 1 of 7	ENSP00000310127.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	10
DANN	Benign	0.68
DEOGEN2	Benign	0.41	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.051	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.39	N
PhyloP100		-0.014
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.34	N
REVEL	Benign	0.27
Sift	Benign	0.97	T
Sift4G	Benign	0.72	T
Polyphen		0.0010	B
Vest4		0.13
MutPred		0.49		Loss of MoRF binding (P = 0.0814)
MVP		0.87
MPC		0.41
ClinPred		0.13	T
GERP RS		-3.7
PromoterAI		0.0012	Neutral
Varity_R		0.14
gMVP		0.14
Mutation Taster		=92/8	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: rs76863988; hg19: chr19-50167954;