rs148672096

Variant names:

• chr19-49660724-C-A
• rs148672096
• NM_001571.6:c.1087G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-49660724-C-A
• chr19-49660724-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001571.6(IRF3):​c.1087G>T​(p.Val363Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V363M) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IRF3 NM_001571.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27609494).

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.1087G>T	p.Val363Leu	missense	Exon 7 of 8	NP_001562.1	Q14653-1
	IRF3	NM_001197122.2		c.1103G>T	p.Arg368Leu	missense	Exon 7 of 8	NP_001184051.1	Q14653-4
	IRF3	NM_001197123.2		c.982G>T	p.Val328Leu	missense	Exon 7 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.1087G>T	p.Val363Leu	missense	Exon 7 of 8	ENSP00000366344.3	Q14653-1
	IRF3	ENST00000601291.5	TSL:1	c.1103G>T	p.Arg368Leu	missense	Exon 7 of 8	ENSP00000471896.1	Q14653-4
	IRF3	ENST00000309877.11	TSL:1	c.1087G>T	p.Val363Leu	missense	Exon 6 of 7	ENSP00000310127.6	Q14653-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000868 AC: 2 AN: 230458 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000312

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000966

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449562 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 719822

African (AFR) AF: 0.00 AC: 0 AN: 33338

American (AMR) AF: 0.0000235 AC: 1 AN: 42616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25746

East Asian (EAS) AF: 0.00 AC: 0 AN: 39204

South Asian (SAS) AF: 0.00 AC: 0 AN: 83686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106724

Other (OTH) AF: 0.00 AC: 0 AN: 59952

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	18
DANN	Uncertain	1.0
Eigen	Benign	0.082
Eigen_PC	Benign	0.050
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.36	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.28	T
PhyloP100		1.1
PrimateAI	Benign	0.20	T
Sift4G	Benign	0.23	T
Vest4		0.23
MVP		0.88
MPC		0.48
ClinPred		0.36	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.29
gMVP		0.53
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs148672096; hg19: chr19-50163981;