ENST00000601291.5:c.1225C>T

Variant names:

• chr19-49659723-G-A
• rs11554833
• ENST00000601291.5:c.1225C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000601291.5(IRF3):​c.1225C>T​(p.His409Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,613,928 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0077 (13 hom., cov: 31)
  • Exomes 𝑓: 0.00073 (14 hom.)
• Consequence: IRF3 ENST00000601291.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.499
• Publications: 2 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004697025).
• BP6: Variant 19-49659723-G-A is Benign according to our data. Variant chr19-49659723-G-A is described in ClinVar as Benign. ClinVar VariationId is 3039781.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00766 (1166/152188) while in subpopulation AFR AF = 0.0269 (1116/41498). AF 95% confidence interval is 0.0256. There are 13 homozygotes in GnomAd4. There are 543 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1166 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000601291.5. 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.1209C>T	p.Leu403Leu	synonymous	Exon 8 of 8	NP_001562.1	Q14653-1
	IRF3	NM_001197122.2		c.1225C>T	p.His409Tyr	missense	Exon 8 of 8	NP_001184051.1	Q14653-4
	IRF3	NM_001197123.2		c.1104C>T	p.Leu368Leu	synonymous	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.1225C>T	p.His409Tyr	missense	Exon 8 of 8	ENSP00000471896.1	Q14653-4
	IRF3	ENST00000377139.8	TSL:1 MANE Select	c.1209C>T	p.Leu403Leu	synonymous	Exon 8 of 8	ENSP00000366344.3	Q14653-1
	IRF3	ENST00000309877.11	TSL:1	c.1209C>T	p.Leu403Leu	synonymous	Exon 7 of 7	ENSP00000310127.6	Q14653-1

Frequencies

GnomAD3 genomes AF: 0.00765 AC: 1164 AN: 152070 Hom.: 13 Cov.: 31

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00196 AC: 492 AN: 251146 AF XY: 0.00147

Gnomad AFR exome AF: 0.0269

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000732 AC: 1070 AN: 1461740 Hom.: 14 Cov.: 33 AF XY: 0.000615 AC XY: 447 AN XY: 727184

African (AFR) AF: 0.0270 AC: 903 AN: 33480

American (AMR) AF: 0.00132 AC: 59 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111920

Other (OTH) AF: 0.00154 AC: 93 AN: 60384

GnomAD4 genome AF: 0.00766 AC: 1166 AN: 152188 Hom.: 13 Cov.: 31 AF XY: 0.00730 AC XY: 543 AN XY: 74412

African (AFR) AF: 0.0269 AC: 1116 AN: 41498

American (AMR) AF: 0.00262 AC: 40 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

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: 0.0000294 AC: 2 AN: 67998

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00309 Hom.: 6

Bravo AF: 0.00898

ESP6500AA AF: 0.0236 AC: 104

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00251 AC: 305

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	IRF3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	5.7
DANN	Benign	0.85
DEOGEN2	Benign	0.021	T
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0047	T
PhyloP100		0.50
PrimateAI	Benign	0.35	T
Sift4G	Benign	0.16	T
Vest4		0.47
MVP		0.94
MPC		0.55
GERP RS		0.55
gMVP		0.36
Mutation Taster		=95/5	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: rs11554833; hg19: chr19-50162980;