rs7251

Variant names:

• chr19-49659652-C-G
• rs7251
• NM_001571.6:c.1280G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-49659652-C-G
• chr19-49659652-C-A
• chr19-49659652-C-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001571.6(IRF3):​c.1280G>C​(p.Ser427Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 1,611,434 control chromosomes in the GnomAD database, including 106,655 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.43 (16020 hom., cov: 31)
  • Exomes 𝑓: 0.34 (90635 hom.)
• Consequence: IRF3 NM_001571.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.636
• Publications: 88 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.883909E-6).
• BP6: Variant 19-49659652-C-G is Benign according to our data. Variant chr19-49659652-C-G is described in ClinVar as Benign. ClinVar VariationId is 2688047.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.654 is higher than 0.05.

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.1280G>C	p.Ser427Thr	missense	Exon 8 of 8	NP_001562.1	Q14653-1
	IRF3	NM_001197122.2		c.1296G>C	p.Glu432Asp	missense	Exon 8 of 8	NP_001184051.1	Q14653-4
	IRF3	NM_001197123.2		c.1175G>C	p.Ser392Thr	missense	Exon 8 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.1280G>C	p.Ser427Thr	missense	Exon 8 of 8	ENSP00000366344.3	Q14653-1
	IRF3	ENST00000601291.5	TSL:1	c.1296G>C	p.Glu432Asp	missense	Exon 8 of 8	ENSP00000471896.1	Q14653-4
	IRF3	ENST00000309877.11	TSL:1	c.1280G>C	p.Ser427Thr	missense	Exon 7 of 7	ENSP00000310127.6	Q14653-1

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65728 AN: 151832 Hom.: 15970 Cov.: 31

Gnomad AFR AF: 0.660

Gnomad AMI AF: 0.415

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.327

Gnomad OTH AF: 0.420

GnomAD2 exomes AF: 0.387 AC: 95034 AN: 245682 AF XY: 0.382

Gnomad AFR exome AF: 0.668

Gnomad AMR exome AF: 0.473

Gnomad ASJ exome AF: 0.357

Gnomad EAS exome AF: 0.351

Gnomad FIN exome AF: 0.264

Gnomad NFE exome AF: 0.328

Gnomad OTH exome AF: 0.370

GnomAD4 exome AF: 0.344 AC: 502778 AN: 1459486 Hom.: 90635 Cov.: 38 AF XY: 0.347 AC XY: 252061 AN XY: 725904

African (AFR) AF: 0.669 AC: 22369 AN: 33456

American (AMR) AF: 0.467 AC: 20680 AN: 44246

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 9257 AN: 26062

East Asian (EAS) AF: 0.365 AC: 14443 AN: 39620

South Asian (SAS) AF: 0.469 AC: 40339 AN: 86074

European-Finnish (FIN) AF: 0.261 AC: 13882 AN: 53236

Middle Eastern (MID) AF: 0.485 AC: 2788 AN: 5744

European-Non Finnish (NFE) AF: 0.321 AC: 356635 AN: 1110766

Other (OTH) AF: 0.371 AC: 22385 AN: 60282

GnomAD4 genome AF: 0.433 AC: 65829 AN: 151948 Hom.: 16020 Cov.: 31 AF XY: 0.429 AC XY: 31853 AN XY: 74294

African (AFR) AF: 0.661 AC: 27364 AN: 41418

American (AMR) AF: 0.439 AC: 6699 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 1224 AN: 3468

East Asian (EAS) AF: 0.354 AC: 1827 AN: 5154

South Asian (SAS) AF: 0.494 AC: 2382 AN: 4826

European-Finnish (FIN) AF: 0.253 AC: 2673 AN: 10580

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.328 AC: 22248 AN: 67922

Other (OTH) AF: 0.425 AC: 895 AN: 2108

Alfa AF: 0.357 Hom.: 3182

Bravo AF: 0.456

TwinsUK AF: 0.324 AC: 1203

ALSPAC AF: 0.314 AC: 1211

ESP6500AA AF: 0.663 AC: 2920

ESP6500EA AF: 0.316 AC: 2715

ExAC AF: 0.390 AC: 47254

Asia WGS AF: 0.507 AC: 1759 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	0.24
DANN	Benign	0.35
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.0000029	T
PhyloP100		-0.64
PrimateAI	Benign	0.26	T
Vest4		0.041
MPC		0.48
ClinPred		0.00066	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.060
Mutation Taster		=100/0	polymorphism (auto)

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: rs7251; hg19: chr19-50162909; COSMIC: COSV59190729; COSMIC: COSV59190729;