NM_001571.6:c.1025A>G

Variant names:

• chr19-49660786-T-C
• rs1057506192
• NM_001571.6:c.1025A>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PP3_Moderate BP6_Moderate BS2

The NM_001571.6(IRF3):​c.1025A>G​(p.Tyr342Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,610,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: IRF3 NM_001571.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.02

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 Likely_benign. Variant got -4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• BP6: Variant 19-49660786-T-C is Benign according to our data. Variant chr19-49660786-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3530021.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF3	NM_001571.6	c.1025A>G	p.Tyr342Cys	missense_variant	Exon 7 of 8	ENST00000377139.8	NP_001562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF3	ENST00000377139.8	c.1025A>G	p.Tyr342Cys	missense_variant	Exon 7 of 8	1	NM_001571.6	ENSP00000366344.3

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152122 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00000410 AC: 1 AN: 243866 Hom.: 0 AF XY: 0.00000760 AC XY: 1 AN XY: 131590

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000343 AC: 5 AN: 1458478 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 725034

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000452

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152122 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8 AN XY: 74320

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000852

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.000151

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Sep 30, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;D;D;D;.;D;.;.;D;D;D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.93	D;.;.;D;D;.;.;D;.;.;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	2.0	.;M;M;M;.;.;.;.;.;.;.
PROVEAN	Pathogenic	-6.2	.;D;D;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.84
Sift	Benign	0.20	.;T;T;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.013	D;T;T;T;D;D;D;D;D;D;.
Polyphen		1.0	.;D;D;D;.;.;.;.;.;.;.
Vest4		0.83
MutPred		0.80		.;Loss of disorder (P = 0.1004);Loss of disorder (P = 0.1004);Loss of disorder (P = 0.1004);.;.;.;.;.;.;.;
MVP		0.98
ClinPred		0.60	D
GERP RS		3.5
Varity_R		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057506192; hg19: chr19-50164043;