11-614892-C-T

Variant names:

• chr11-614892-C-T
• rs752300122
• NM_001572.5:c.299G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001572.5(IRF7):​c.299G>A​(p.Arg100His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IRF7 NM_001572.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.04

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15037623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF7	NM_001572.5	c.299G>A	p.Arg100His	missense_variant	Exon 4 of 11	ENST00000525445.6	NP_001563.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF7	ENST00000525445.6	c.299G>A	p.Arg100His	missense_variant	Exon 4 of 11	5	NM_001572.5	ENSP00000434009.2

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1434272 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 711924

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency 39 Uncertain:1

Jan 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 113 of the IRF7 protein (p.Arg113His). 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. 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	0.074
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	7.3
DANN	Benign	0.96
DEOGEN2	Uncertain	0.49	T;.;.;T;T;.;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.74	.;T;T;T;T;.;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	0.075	N;.;N;N;.;.;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.56	N;N;N;.;.;N;.;.
REVEL	Uncertain	0.31
Sift	Benign	0.38	T;T;T;.;.;T;.;.
Sift4G	Benign	0.33	T;T;T;.;T;T;.;.
Polyphen		0.0060	B;B;B;B;.;B;.;.
Vest4		0.099
MutPred		0.61		Loss of MoRF binding (P = 0.0575);.;Loss of MoRF binding (P = 0.0575);Loss of MoRF binding (P = 0.0575);.;.;Loss of MoRF binding (P = 0.0575);.;
MVP		0.63
MPC		0.13
ClinPred		0.063	T
GERP RS		-8.8
Varity_R		0.035
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs752300122; hg19: chr11-614892;