rs369330126

Positions:

• chr11-613951-C-A
• chr11-613951-C-G
• chr11-613951-C-T

Variant summary

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

The NM_001572.5(IRF7):​c.766G>T​(p.Gly256Cys) variant causes a missense, splice region 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IRF7 NM_001572.5 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.27

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	Protein	UniProt
IRF7	NM_001572.5	c.766G>T	p.Gly256Cys	missense_variant, splice_region_variant	7/11	ENST00000525445.6	NP_001563.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRF7	ENST00000525445.6	c.766G>T	p.Gly256Cys	missense_variant, splice_region_variant	7/11	5	NM_001572.5	ENSP00000434009	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Labcorp Genetics (formerly Invitae), Labcorp

May 30, 2018

This sequence change replaces glycine with cysteine at codon 269 of the IRF7 protein (p.Gly269Cys). The glycine residue is weakly conserved and there is a large physicochemical difference between glycine and cysteine. This variant also falls at the last nucleotide of exon 5 of the IRF7 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with IRF7-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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	0.15
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T;.;T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.58	.;T;T;.
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	1.8	L;.;L;.
MutationTaster	Benign	1.0	D;D;D;N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.6	N;N;.;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.021	D;D;.;D
Sift4G	Uncertain	0.036	D;D;.;D
Polyphen		1.0	D;D;D;D
Vest4		0.37
MutPred		0.24		Loss of glycosylation at T254 (P = 0.0422);.;Loss of glycosylation at T254 (P = 0.0422);.;
MVP		0.87
MPC		0.52
ClinPred		0.77	D
GERP RS		2.4
Varity_R		0.14
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.63		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.63		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs369330126; hg19: chr11-613951;