19-49660724-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001571.6(IRF3):​c.1087G>A​(p.Val363Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000845 in 1,601,776 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V363L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0040 (4 hom., cov: 31)
  • Exomes 𝑓: 0.00052 (5 hom.)
• Consequence: IRF3 NM_001571.6 missense
• Clinical Significance: Benign criteria provided, single submitter B: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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00916487).
• BP6: Variant 19-49660724-C-T is Benign according to our data. Variant chr19-49660724-C-T is described in ClinVar as Benign. ClinVar VariationId is 4083782.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 606 AD gene.

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>A	p.Val363Met	missense	Exon 7 of 8	NP_001562.1	Q14653-1
	IRF3	NM_001197122.2		c.1103G>A	p.Arg368His	missense	Exon 7 of 8	NP_001184051.1	Q14653-4
	IRF3	NM_001197123.2		c.982G>A	p.Val328Met	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>A	p.Val363Met	missense	Exon 7 of 8	ENSP00000366344.3	Q14653-1
	IRF3	ENST00000601291.5	TSL:1	c.1103G>A	p.Arg368His	missense	Exon 7 of 8	ENSP00000471896.1	Q14653-4
	IRF3	ENST00000309877.11	TSL:1	c.1087G>A	p.Val363Met	missense	Exon 6 of 7	ENSP00000310127.6	Q14653-1

Frequencies

GnomAD3 genomes AF: 0.00398 AC: 605 AN: 152096 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00432

GnomAD2 exomes AF: 0.00135 AC: 311 AN: 230458 AF XY: 0.00102

Gnomad AFR exome AF: 0.0154

Gnomad AMR exome AF: 0.00209

Gnomad ASJ exome AF: 0.000211

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000135

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000515 AC: 747 AN: 1449562 Hom.: 5 Cov.: 30 AF XY: 0.000421 AC XY: 303 AN XY: 719822

African (AFR) AF: 0.0142 AC: 472 AN: 33338

American (AMR) AF: 0.00214 AC: 91 AN: 42616

Ashkenazi Jewish (ASJ) AF: 0.000466 AC: 12 AN: 25746

East Asian (EAS) AF: 0.0000510 AC: 2 AN: 39204

South Asian (SAS) AF: 0.0000836 AC: 7 AN: 83686

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

Middle Eastern (MID) AF: 0.000872 AC: 5 AN: 5736

European-Non Finnish (NFE) AF: 0.0000831 AC: 92 AN: 1106724

Other (OTH) AF: 0.00110 AC: 66 AN: 59952

GnomAD4 genome AF: 0.00398 AC: 606 AN: 152214 Hom.: 4 Cov.: 31 AF XY: 0.00403 AC XY: 300 AN XY: 74420

African (AFR) AF: 0.0137 AC: 568 AN: 41524

American (AMR) AF: 0.00137 AC: 21 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68008

Other (OTH) AF: 0.00427 AC: 9 AN: 2106

Alfa AF: 0.00167 Hom.: 2

Bravo AF: 0.00481

ESP6500AA AF: 0.0116 AC: 51

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00157 AC: 190

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0092	T
PhyloP100		1.1
PrimateAI	Benign	0.20	T
Sift4G	Benign	0.13	T
Vest4		0.23
MVP		0.97
MPC		0.53
ClinPred		0.044	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
gMVP		0.44
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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;