19-49659618-G-C

Variant names:

• chr19-49659618-G-C
• rs370098271
• ENST00000601291.5:c.1330C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001197122.2(IRF3):​c.1330C>G​(p.Pro444Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,595,342 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: IRF3 NM_001197122.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.256
• Publications: 1 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09765819).
• BS2: High AC in GnomAd4 at 12 AD gene.

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.*30C>G		3_prime_UTR	Exon 8 of 8	NP_001562.1	Q14653-1
	IRF3	NM_001197122.2		c.1330C>G	p.Pro444Ala	missense	Exon 8 of 8	NP_001184051.1	Q14653-4
	IRF3	NM_001197123.2		c.*30C>G		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.1330C>G	p.Pro444Ala	missense	Exon 8 of 8	ENSP00000471896.1	Q14653-4
	IRF3	ENST00000377139.8	TSL:1 MANE Select	c.*30C>G		3_prime_UTR	Exon 8 of 8	ENSP00000366344.3	Q14653-1
	IRF3	ENST00000309877.11	TSL:1	c.*30C>G		3_prime_UTR	Exon 7 of 7	ENSP00000310127.6	Q14653-1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1443072 Hom.: 0 Cov.: 30 AF XY: 0.00000279 AC XY: 2 AN XY: 716438

African (AFR) AF: 0.000152 AC: 5 AN: 32962

American (AMR) AF: 0.00 AC: 0 AN: 40948

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25656

East Asian (EAS) AF: 0.00 AC: 0 AN: 38650

South Asian (SAS) AF: 0.00 AC: 0 AN: 84114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102988

Other (OTH) AF: 0.00 AC: 0 AN: 59734

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74454

African (AFR) AF: 0.000289 AC: 12 AN: 41540

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000567

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

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	0.061
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	1.1
DANN	Benign	0.66
DEOGEN2	Benign	0.0081	T
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.098	T
PhyloP100		0.26
PrimateAI	Benign	0.25	T
Vest4		0.13
MVP		1.0
MPC		0.76
GERP RS		0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.044
Mutation Taster		=96/4	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: rs370098271; hg19: chr19-50162875;