11-612667-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001572.5(IRF7):c.1490T>C(p.Met497Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,824 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IRF7 NM_001572.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF7	NM_001572.5	c.1490T>C	p.Met497Thr	missense_variant	11/11	ENST00000525445.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF7	ENST00000525445.6	c.1490T>C	p.Met497Thr	missense_variant	11/11	5	NM_001572.5	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460824 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726740

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jul 17, 2023

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 510 of the IRF7 protein (p.Met510Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IRF7-related conditions. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	22
Dann	Benign	0.85
DEOGEN2	Benign	0.41	T;.;.;T;T;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.083
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	1.8	L;.;.;L;.;.
MutationTaster	Benign	0.83	N;N;N;N;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.7	D;D;D;.;.;D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;D;D;.;.;D
Sift4G	Uncertain	0.010	D;D;D;.;D;D
Polyphen		0.99	D;D;D;D;.;D
Vest4		0.46
MutPred		0.40		Gain of relative solvent accessibility (P = 0.0215);.;.;Gain of relative solvent accessibility (P = 0.0215);.;.;
MVP		0.97
MPC		0.56
ClinPred		0.78	D
GERP RS		3.3
Varity_R		0.63
gMVP		0.45

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: rs1298847378; hg19: chr11-612667;