NM_002163.4:c.9C>G

Variant names:

• chr16-85903024-C-G
• rs886039596
• NM_002163.4:c.9C>G

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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]

IRF8 Gene-Disease associations (from GenCC):

• Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Illumina
• immunodeficiency 32B

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002163.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF8	NM_002163.4	MANE Select	c.9C>G	p.Asp3Glu	missense	Exon 2 of 9	NP_002154.1	Q02556
	IRF8	NM_001363907.1		c.39C>G	p.Asp13Glu	missense	Exon 2 of 9	NP_001350836.1
	IRF8	NM_001363908.1		c.-498C>G		5_prime_UTR	Exon 1 of 7	NP_001350837.1	H3BRT4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF8	ENST00000268638.10	TSL:1 MANE Select	c.9C>G	p.Asp3Glu	missense	Exon 2 of 9	ENSP00000268638.4	Q02556
	IRF8	ENST00000563180.1	TSL:1	c.9C>G	p.Asp3Glu	missense	Exon 1 of 2	ENSP00000458047.1	H3BVC2
	IRF8	ENST00000564803.6	TSL:2	c.9C>G	p.Asp3Glu	missense	Exon 2 of 9	ENSP00000456992.2	Q02556

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.067
Eigen_PC	Benign	-0.015
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.1	L
PhyloP100		0.95
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.29	N
REVEL	Uncertain	0.39
Sift	Benign	0.18	T
Sift4G	Benign	0.37	T
Polyphen		0.71	P
Vest4		0.34
MutPred		0.28		Gain of solvent accessibility (P = 0.0306)
MVP		0.80
MPC		1.4
ClinPred		0.91	D
GERP RS		3.6
PromoterAI		-0.025	Neutral
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

Other links and lift over

dbSNP: rs886039596; hg19: chr16-85936630;