rs143769046

chr19-49662101-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001571.6(IRF3):c.829G>A(p.Ala277Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00605 in 1,613,680 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0062 (39 hom.)
• Consequence: IRF3 NM_001571.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.533

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

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011467636).
• BP6: Variant 19-49662101-C-T is Benign according to our data. Variant chr19-49662101-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 495307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49662101-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 671 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF3	NM_001571.6	c.829G>A	p.Ala277Thr	missense_variant	6/8	ENST00000377139.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF3	ENST00000377139.8	c.829G>A	p.Ala277Thr	missense_variant	6/8	1	NM_001571.6	P1

Frequencies

GnomAD3 genomes AF: 0.00441 AC: 671 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.0538

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00650

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00394 AC: 988 AN: 250464 Hom.: 5 AF XY: 0.00385 AC XY: 521 AN XY: 135468

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00420

Gnomad ASJ exome AF: 0.000597

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.00283

Gnomad NFE exome AF: 0.00615

Gnomad OTH exome AF: 0.00490

GnomAD4 exome AF: 0.00622 AC: 9088 AN: 1461312 Hom.: 39 Cov.: 31 AF XY: 0.00607 AC XY: 4409 AN XY: 726898

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00515

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00136

Gnomad4 FIN exome AF: 0.00304

Gnomad4 NFE exome AF: 0.00742

Gnomad4 OTH exome AF: 0.00451

GnomAD4 genome AF: 0.00440 AC: 671 AN: 152368 Hom.: 0 Cov.: 33 AF XY: 0.00434 AC XY: 323 AN XY: 74504

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00601

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00650

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00513 Hom.: 1

Bravo AF: 0.00467

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00362 AC: 439

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00567

EpiControl AF: 0.00646

ClinVar

Significance: Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	IRF3: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

IRF3-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 16, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 7 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Mar 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	5.8
Dann	Benign	0.93
DEOGEN2	Benign	0.30	T;T;.;.;T;T;T;T;T;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.84	T;.;T;T;.;T;.;.;.;T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.011	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T;T;T
Polyphen		0.21	.;B;.;.;B;B;.;.;.;.
Vest4		0.14
MVP		0.95
MPC		0.54
ClinPred		0.0089	T
GERP RS		-0.52
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.0
Varity_R		0.14
gMVP		0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs143769046; hg19: chr19-50165358;