rs201379782

Positions:

chr11-613978-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001572.5(IRF7):c.739G>A(p.Gly247Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000528 in 1,606,940 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.00060 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00052 ( 5 hom. )

Consequence

IRF7
NM_001572.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: -1.28

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:

IRF7 (HGNC:):

IRF7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007898957).

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRF7	NM_001572.5 linkuse as main transcript	c.739G>A	p.Gly247Arg	missense_variant	7/11	ENST00000525445.6	NP_001563.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRF7	ENST00000525445.6 linkuse as main transcript	c.739G>A	p.Gly247Arg	missense_variant	7/11	5	NM_001572.5	ENSP00000434009.2		Q92985-1

Frequencies

GnomAD3 genomes

AF:

0.000606

AC:

AN:

151910

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.000486

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000717

AC:

165

AN:

230188

Hom.:

AF XY:

0.000725

AC XY:

AN XY:

126978

show subpopulations

Gnomad AFR exome

AF:

0.0000718

Gnomad AMR exome

AF:

0.000831

Gnomad ASJ exome

AF:

0.00160

Gnomad EAS exome

AF:

0.0000565

Gnomad SAS exome

AF:

0.000336

Gnomad FIN exome

AF:

0.00117

Gnomad NFE exome

AF:

0.000713

Gnomad OTH exome

AF:

0.00269

GnomAD4 exome

AF:

0.000520

AC:

757

AN:

1454912

Hom.:

Cov.:

AF XY:

0.000554

AC XY:

401

AN XY:

723770

show subpopulations

Gnomad4 AFR exome

AF:

0.000241

Gnomad4 AMR exome

AF:

0.00116

Gnomad4 ASJ exome

AF:

0.00105

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000537

Gnomad4 FIN exome

AF:

0.000812

Gnomad4 NFE exome

AF:

0.000369

Gnomad4 OTH exome

AF:

0.00137

GnomAD4 genome

AF:

0.000599

AC:

AN:

152028

Hom.:

Cov.:

AF XY:

0.000632

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00170

Gnomad4 NFE

AF:

0.000486

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000487

Hom.:

Bravo

AF:

0.000525

ESP6500AA

AF:

0.000229

AC:

ESP6500EA

AF:

0.000585

AC:

ExAC

AF:

0.000631

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Immunodeficiency 39

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 260 of the IRF7 protein (p.Gly260Arg). This variant is present in population databases (rs201379782, gnomAD 0.2%), 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: 569741). 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 arginine 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	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 02, 2022	IRF7 NM_004031.2 exon 5 p.Gly260Arg (c.778G>A): This variant has not been reported in the literature but is present in 0.1% (18/10608) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-613978-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:569741). This variant amino acid Arginine (Arg) is present in several species including multiple mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not provided

Uncertain:1Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2021

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. -

IRF7-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 03, 2022

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.30

CADD

Benign

0.13

DANN

Benign

0.58

DEOGEN2

Benign

0.057

T;.;T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.61

.;T;T;.

M_CAP

Benign

0.036

MetaRNN

Benign

0.0079

T;T;T;T

MetaSVM

Uncertain

-0.080

MutationAssessor

Benign

0.14

N;.;N;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.10

N;N;.;N

REVEL

Benign

0.21

Sift

Benign

0.56

T;T;.;T

Sift4G

Benign

0.49

T;T;.;T

Polyphen

0.0

B;B;B;B

Vest4

0.13

MutPred

0.27

Loss of catalytic residue at Q249 (P = 0.0895);.;Loss of catalytic residue at Q249 (P = 0.0895);.;

MVP

0.52

MPC

0.13

ClinPred

0.0095

GERP RS

-5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.068

gMVP

0.34

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

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