rs201379782

chr11-613978-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: -1.28

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007898957).
• BP6: Variant 11-613978-C-T is Benign according to our data. Variant chr11-613978-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 569741.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}. Variant chr11-613978-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF7	NM_001572.5	c.739G>A	p.Gly247Arg	missense_variant	7/11	ENST00000525445.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF7	ENST00000525445.6	c.739G>A	p.Gly247Arg	missense_variant	7/11	5	NM_001572.5	P2

Frequencies

GnomAD3 genomes AF: 0.000606 AC: 92 AN: 151910 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000725 AC XY: 92 AN XY: 126978

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.: 5 Cov.: 34 AF XY: 0.000554 AC XY: 401 AN XY: 723770

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: 91 AN: 152028 Hom.: 0 Cov.: 32 AF XY: 0.000632 AC XY: 47 AN XY: 74336

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.: 0

Bravo AF: 0.000525

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.000585 AC: 5

ExAC AF: 0.000631 AC: 76

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Immunodeficiency 39 Uncertain:3

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	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	Fulgent Genetics, Fulgent Genetics	Mar 18, 2022	- -

not provided Benign: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	-	- -

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, criteria provided, single submitter

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	T
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	N
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.0079	T;T;T;T
MetaSVM	Uncertain	-0.080	T
MutationAssessor	Benign	0.14	N;.;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.42	T
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	T
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

Other links and lift over

dbSNP: rs201379782; hg19: chr11-613978; COSMIC: COSV52756792; COSMIC: COSV52756792;