chr19-49660812-C-G

Variant names:

• chr19-49660812-C-G
• rs758305171
• ENST00000601291.5:c.1015G>C

Variant summary

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

The NM_001197122.2(IRF3):​c.1015G>C​(p.Gly339Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,450,824 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: IRF3 NM_001197122.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.23
• 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: 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=0.08048603).

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.999G>C	p.Thr333Thr	synonymous	Exon 7 of 8	NP_001562.1	Q14653-1
	IRF3	NM_001197122.2		c.1015G>C	p.Gly339Arg	missense	Exon 7 of 8	NP_001184051.1	Q14653-4
	IRF3	NM_001197123.2		c.894G>C	p.Thr298Thr	synonymous	Exon 7 of 8	NP_001184052.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF3	ENST00000601291.5	TSL:1	c.1015G>C	p.Gly339Arg	missense	Exon 7 of 8	ENSP00000471896.1	Q14653-4
	IRF3	ENST00000377139.8	TSL:1 MANE Select	c.999G>C	p.Thr333Thr	synonymous	Exon 7 of 8	ENSP00000366344.3	Q14653-1
	IRF3	ENST00000309877.11	TSL:1	c.999G>C	p.Thr333Thr	synonymous	Exon 6 of 7	ENSP00000310127.6	Q14653-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00 AC: 0 AN: 230052 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1450824 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 720456

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 42864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25808

East Asian (EAS) AF: 0.00 AC: 0 AN: 39344

South Asian (SAS) AF: 0.00 AC: 0 AN: 83892

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1107164

Other (OTH) AF: 0.00 AC: 0 AN: 60022

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	0.0066	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	0.30
DANN	Benign	0.68
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.080	T
PhyloP100		-2.2
PrimateAI	Benign	0.24	T
Sift4G	Benign	0.14	T
Vest4		0.14
MVP		0.76
MPC		0.45
GERP RS		-9.1
gMVP		0.68
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs758305171; hg19: chr19-50164069;