11-614874-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001572.5(IRF7):c.317T>A(p.Val106Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000919 in 1,578,572 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V106M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000041 (1 hom.)
• Consequence: IRF7 NM_001572.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.205

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.012406707).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF7	NM_001572.5	c.317T>A	p.Val106Glu	missense_variant	4/11	ENST00000525445.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF7	ENST00000525445.6	c.317T>A	p.Val106Glu	missense_variant	4/11	5	NM_001572.5	P2

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152184 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000120 AC: 22 AN: 183330 Hom.: 0 AF XY: 0.0000998 AC XY: 10 AN XY: 100166

Gnomad AFR exome AF: 0.00196

Gnomad AMR exome AF: 0.0000341

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000209

GnomAD4 exome AF: 0.0000414 AC: 59 AN: 1426270 Hom.: 1 Cov.: 37 AF XY: 0.0000396 AC XY: 28 AN XY: 706910

Gnomad4 AFR exome AF: 0.00163

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000102

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152302 Hom.: 0 Cov.: 35 AF XY: 0.000362 AC XY: 27 AN XY: 74484

Gnomad4 AFR AF: 0.00180

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000335 Hom.: 0

Bravo AF: 0.000616

ESP6500AA AF: 0.000931 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000152 AC: 18

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency 39 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 119 of the IRF7 protein (p.Val119Glu). This variant is present in population databases (rs376350717, 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: 565325). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt IRF7 protein function with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	16
Dann	Benign	0.68
DEOGEN2	Uncertain	0.52	D;.;.;D;T;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.26	N
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.012	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	0.59	N;.;N;N;.;.;.;.
MutationTaster	Benign	0.65	D;D;D;D;N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.0	N;N;N;.;.;N;.;.
REVEL	Uncertain	0.36
Sift	Benign	0.10	T;T;T;.;.;T;.;.
Sift4G	Benign	1.0	T;T;T;.;T;T;.;.
Polyphen		0.99	D;B;B;D;.;B;.;.
Vest4		0.23
MVP		0.52
MPC		0.21
ClinPred		0.0050	T
GERP RS		0.45
Varity_R		0.16
gMVP		0.41

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: rs376350717; hg19: chr11-614874;