rs143769046

Variant names:

• chr19-49662101-C-T
• rs143769046
• NM_001571.6:c.829G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0044 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0062 (39 hom.)
• Consequence: IRF3 NM_001571.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4 O:1
• Conservation: PhyloP100: -0.533
• Publications: 12 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 -9 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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 495307.
• BS2: High AC in GnomAd4 at 671 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF3	NM_001571.6	MANE Select	c.829G>A	p.Ala277Thr	missense	Exon 6 of 8	NP_001562.1
	IRF3	NM_001197122.2		c.829G>A	p.Ala277Thr	missense	Exon 6 of 8	NP_001184051.1
	IRF3	NM_001197123.2		c.724G>A	p.Ala242Thr	missense	Exon 6 of 8	NP_001184052.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF3	ENST00000377139.8	TSL:1 MANE Select	c.829G>A	p.Ala277Thr	missense	Exon 6 of 8	ENSP00000366344.3
	IRF3	ENST00000601291.5	TSL:1	c.829G>A	p.Ala277Thr	missense	Exon 6 of 8	ENSP00000471896.1
	IRF3	ENST00000309877.11	TSL:1	c.829G>A	p.Ala277Thr	missense	Exon 5 of 7	ENSP00000310127.6

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

GnomAD2 exomes AF: 0.00394 AC: 988 AN: 250464 AF XY: 0.00385

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 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

African (AFR) AF: 0.000687 AC: 23 AN: 33472

American (AMR) AF: 0.00515 AC: 230 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00136 AC: 117 AN: 86242

European-Finnish (FIN) AF: 0.00304 AC: 162 AN: 53282

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5764

European-Non Finnish (NFE) AF: 0.00742 AC: 8244 AN: 1111684

Other (OTH) AF: 0.00451 AC: 272 AN: 60366

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

African (AFR) AF: 0.00111 AC: 46 AN: 41584

American (AMR) AF: 0.00601 AC: 92 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

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

South Asian (SAS) AF: 0.000827 AC: 4 AN: 4834

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10632

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

European-Non Finnish (NFE) AF: 0.00650 AC: 442 AN: 68034

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00451 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: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IRF3: BS1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 14, 2018

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Sep 25, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

IRF3-related disorder Benign:1

Mar 16, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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).

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-0.53
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.54	N
REVEL	Uncertain	0.36
Sift	Benign	0.34	T
Sift4G	Benign	0.13	T
Polyphen		0.21	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
Mutation Taster		=81/19	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: rs143769046; hg19: chr19-50165358; COSMIC: COSV106083179; COSMIC: COSV106083179;