16-85903024-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002163.4(IRF8):c.9C>G(p.Asp3Glu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IRF8 NM_002163.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.953

Genes affected

IRF8 (HGNC:5358): (interferon regulatory factor 8) Interferon consensus sequence-binding protein (ICSBP) is a transcription factor of the interferon (IFN) regulatory factor (IRF) family. Proteins of this family are composed of a conserved DNA-binding domain in the N-terminal region and a divergent C-terminal region that serves as the regulatory domain. The IRF family proteins bind to the IFN-stimulated response element (ISRE) and regulate expression of genes stimulated by type I IFNs, namely IFN-alpha and IFN-beta. IRF family proteins also control expression of IFN-alpha and IFN-beta-regulated genes that are induced by viral infection. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32390255).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF8	NM_002163.4	c.9C>G	p.Asp3Glu	missense_variant	2/9	ENST00000268638.10
IRF8	NM_001363907.1	c.39C>G	p.Asp13Glu	missense_variant	2/9
IRF8	XM_047434052.1	c.39C>G	p.Asp13Glu	missense_variant	3/10
IRF8	NM_001363908.1	c.-498C>G		5_prime_UTR_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF8	ENST00000268638.10	c.9C>G	p.Asp3Glu	missense_variant	2/9	1	NM_002163.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 15, 2018

The D3E variant in the IRF8 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). The D3E variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret D3E as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.;T;.;T
Eigen	Benign	-0.067
Eigen_PC	Benign	-0.015
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D;T;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.32	T;T;T;T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.1	L;.;.;.;.
MutationTaster	Benign	0.95	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.29	N;N;N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.18	T;T;T;T;T
Sift4G	Benign	0.37	T;T;T;T;T
Polyphen		0.71	P;.;.;.;.
Vest4		0.34
MutPred		0.28		Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);
MVP		0.80
MPC		1.4
ClinPred		0.91	D
GERP RS		3.6
Varity_R		0.098
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs886039596; hg19: chr16-85936630;