rs1555509293

chr16-85911617-A-G

Variant summary

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

The NM_002163.4(IRF8):c.406A>G(p.Met136Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 4.87

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF8	NM_002163.4	c.406A>G	p.Met136Val	missense_variant	4/9	ENST00000268638.10
IRF8	NM_001363907.1	c.436A>G	p.Met146Val	missense_variant	4/9
IRF8	XM_047434052.1	c.436A>G	p.Met146Val	missense_variant	5/10
IRF8	NM_001363908.1	c.-101A>G		5_prime_UTR_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF8	ENST00000268638.10	c.406A>G	p.Met136Val	missense_variant	4/9	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

Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency;C4016741:Immunodeficiency 32B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 23, 2017

This variant has not been reported in the literature in individuals with IRF8-related disease. 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with valine at codon 136 of the IRF8 protein (p.Met136Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Benign	20
Dann	Benign	0.72
DEOGEN2	Benign	0.31	T;.;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.084
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	1.7	L;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.36	T;T;T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.024	B;.;.
Vest4		0.61
MutPred		0.32		Loss of disorder (P = 0.1301);Loss of disorder (P = 0.1301);Loss of disorder (P = 0.1301);
MVP		0.97
MPC		0.58
ClinPred		0.49	T
GERP RS		5.0
Varity_R		0.18
gMVP		0.44

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: rs1555509293; hg19: chr16-85945223;