rs201036875

chr11-614799-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001572.5(IRF7):c.392G>A(p.Arg131Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000489 in 1,544,066 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (5 hom.)
• Consequence: IRF7 NM_001572.5 missense, splice_region
• Scores: Splicing: ADA: 0.00006317
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: -0.470

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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007612765).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF7	NM_001572.5	c.392G>A	p.Arg131Gln	missense_variant, splice_region_variant	4/11	ENST00000525445.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF7	ENST00000525445.6	c.392G>A	p.Arg131Gln	missense_variant, splice_region_variant	4/11	5	NM_001572.5	P2

Frequencies

GnomAD3 genomes AF: 0.000479 AC: 73 AN: 152268 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000655 AC: 91 AN: 138912 Hom.: 0 AF XY: 0.000545 AC XY: 41 AN XY: 75298

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000859

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000360

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000709

Gnomad OTH exome AF: 0.00271

GnomAD4 exome AF: 0.000491 AC: 683 AN: 1391680 Hom.: 5 Cov.: 31 AF XY: 0.000516 AC XY: 354 AN XY: 686682

Gnomad4 AFR exome AF: 0.000255

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.00104

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000571

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000362

Gnomad4 OTH exome AF: 0.00140

GnomAD4 genome AF: 0.000472 AC: 72 AN: 152386 Hom.: 0 Cov.: 33 AF XY: 0.000496 AC XY: 37 AN XY: 74524

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00101 Hom.: 1

Bravo AF: 0.000518

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000620 AC: 5

ExAC AF: 0.000276 AC: 29

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Immunodeficiency 39 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 144 of the IRF7 protein (p.Arg144Gln). This variant is present in population databases (rs201036875, 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: 573866). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 2 p.Arg144Gln (c.431G>A): This variant has not been reported in the literature but is present in 0.1% (20/15292) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-614799-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:573866). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. 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	Fulgent Genetics, Fulgent Genetics	Mar 18, 2022	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2021

The c.431G>A (p.R144Q) alteration is located in exon 2 (coding exon 2) of the IRF7 gene. This alteration results from a G to A substitution at nucleotide position 431, causing the arginine (R) at amino acid position 144 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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	0.076
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	13
Dann	Benign	0.97
DEOGEN2	Benign	0.042	T;.;.;T;T;.;.;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.19	N
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.0064	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.047	T
MutationAssessor	Benign	1.8	L;.;L;L;.;.;.;.
MutationTaster	Benign	0.74	D;N;N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.41	N;N;N;.;.;N;.;.
REVEL	Benign	0.22
Sift	Benign	0.65	T;T;T;.;.;T;.;.
Sift4G	Benign	0.62	T;T;T;.;T;T;.;.
Polyphen		0.79	P;B;B;P;.;B;.;.
Vest4		0.17
MVP		0.78
MPC		0.29
ClinPred		0.064	T
GERP RS		-0.98
Varity_R		0.025
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000063
dbscSNV1_RF	Benign	0.0020
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

Publications

LitVar

Other links and lift over

dbSNP: rs201036875; hg19: chr11-614799;