rs149039709

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001572.5(IRF7):c.1268G>C(p.Arg423Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000431 in 1,613,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 0 hom. )

Consequence

IRF7
NM_001572.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -1.69

Variant links:

Genes affected

IRF7 (HGNC:6122): (interferon regulatory factor 7) This gene encodes interferon regulatory factor 7, a member of the interferon regulatory transcription factor (IRF) family. It has been shown to play a role in the transcriptional activation of virus-inducible cellular genes, including interferon beta chain genes. Inducible expression of IRF7 is largely restricted to lymphoid tissue. The encoded protein plays an important role in the innate immune response against DNA and RNA viruses. [provided by RefSeq, Jul 2021]

IRF7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07823861).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRF7	NM_001572.5 link	c.1268G>C	p.Arg423Pro	missense_variant	10/11	ENST00000525445.6	NP_001563.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRF7	ENST00000525445.6 link	c.1268G>C	p.Arg423Pro	missense_variant	10/11	5	NM_001572.5	ENSP00000434009.2		Q92985-1

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000272

AC:

AN:

249574

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

135420

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000570

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.000444

AC:

648

AN:

1460738

Hom.:

Cov.:

AF XY:

0.000428

AC XY:

311

AN XY:

726654

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000955

Gnomad4 NFE exome

AF:

0.000558

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000315

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000617

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000447

Hom.:

Bravo

AF:

0.000336

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000206

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Immunodeficiency 39

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 436 of the IRF7 protein (p.Arg436Pro). This variant is present in population databases (rs149039709, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with IRF7-related conditions. ClinVar contains an entry for this variant (Variation ID: 476071). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 23, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.32

CADD

Benign

1.2

DANN

Benign

0.96

DEOGEN2

Uncertain

0.56

D;.;.;D;T;.

Eigen

Benign

-0.95

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.66

.;T;T;T;T;.

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.078

T;T;T;T;T;T

MetaSVM

Uncertain

-0.012

MutationAssessor

Benign

0.95

L;.;.;L;.;.

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-2.6

D;N;N;.;.;N

REVEL

Uncertain

0.29

Sift

Benign

0.13

T;T;T;.;.;T

Sift4G

Benign

0.14

T;T;T;.;T;T

Polyphen

0.83

P;P;B;P;.;P

Vest4

0.11

MVP

0.74

MPC

0.17

ClinPred

0.098

GERP RS

-3.1

Varity_R

0.59

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over