16-85903085-C-G

Variant summary

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

The NM_002163.4(IRF8):c.70C>G(p.Pro24Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IRF8 NM_002163.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.42

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.70C>G	p.Pro24Ala	missense_variant	2/9	ENST00000268638.10
IRF8	NM_001363907.1	c.100C>G	p.Pro34Ala	missense_variant	2/9
IRF8	XM_047434052.1	c.100C>G	p.Pro34Ala	missense_variant	3/10
IRF8	NM_001363908.1	c.-437C>G		5_prime_UTR_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF8	ENST00000268638.10	c.70C>G	p.Pro24Ala	missense_variant	2/9	1	NM_002163.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

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

Jul 21, 2019

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with IRF8-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with alanine at codon 24 of the IRF8 protein (p.Pro24Ala). The proline residue is moderately conserved and there is a small physicochemical difference between proline and alanine. 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	0.11
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.96	D;.;D;.;D
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.024
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.64	D;D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Benign	2.0	M;.;.;.;.
MutationTaster	Benign	0.66	D;D
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D
REVEL	Uncertain	0.47
Sift	Benign	0.14	T;T;T;T;T
Sift4G	Benign	0.51	T;T;T;T;T
Polyphen		0.0090	B;.;.;.;.
Vest4		0.25
MutPred		0.84		Gain of catalytic residue at P24 (P = 0.0134);Gain of catalytic residue at P24 (P = 0.0134);Gain of catalytic residue at P24 (P = 0.0134);Gain of catalytic residue at P24 (P = 0.0134);Gain of catalytic residue at P24 (P = 0.0134);
MVP		0.69
MPC		1.5
ClinPred		0.52	D
GERP RS		4.6
Varity_R		0.15
gMVP		0.22

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: rs1904878101; hg19: chr16-85936691; COSMIC: COSV105097170; COSMIC: COSV105097170;