rs1555509293

Variant names:

• chr16-85911617-A-G
• rs1555509293
• NM_002163.4:c.406A>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, multiple submitters, no conflicts U:2
• 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 rank	MANE	Protein	UniProt
IRF8	NM_002163.4	c.406A>G	p.Met136Val	missense_variant	Exon 4 of 9	ENST00000268638.10	NP_002154.1
IRF8	NM_001363907.1	c.436A>G	p.Met146Val	missense_variant	Exon 4 of 9		NP_001350836.1
IRF8	XM_047434052.1	c.436A>G	p.Met146Val	missense_variant	Exon 5 of 10		XP_047290008.1
IRF8	NM_001363908.1	c.-101A>G		5_prime_UTR_variant	Exon 3 of 7		NP_001350837.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF8	ENST00000268638.10	c.406A>G	p.Met136Val	missense_variant	Exon 4 of 9	1	NM_002163.4	ENSP00000268638.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Sep 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.406A>G (p.M136V) alteration is located in exon 4 (coding exon 3) of the IRF8 gene. This alteration results from a A to G substitution at nucleotide position 406, causing the methionine (M) at amino acid position 136 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Dec 23, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 has not been reported in the literature in individuals with IRF8-related disease. 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;.;.
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;