rs397514711

Positions:

• chr16-85909053-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_002163.4(IRF8):​c.238A>G​(p.Thr80Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T80R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IRF8 NM_002163.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.82

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908
• PP5: Variant 16-85909053-A-G is Pathogenic according to our data. Variant chr16-85909053-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 56843.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF8	NM_002163.4	c.238A>G	p.Thr80Ala	missense_variant	3/9	ENST00000268638.10
IRF8	NM_001363907.1	c.268A>G	p.Thr90Ala	missense_variant	3/9
IRF8	XM_047434052.1	c.268A>G	p.Thr90Ala	missense_variant	4/10
IRF8	NM_001363908.1	c.-269A>G		5_prime_UTR_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF8	ENST00000268638.10	c.238A>G	p.Thr80Ala	missense_variant	3/9	1	NM_002163.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 14, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D;.;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.55	T;T;T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.3	L;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.9	D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;T;T;D
Sift4G	Pathogenic	0.0	D;T;T;D
Polyphen		1.0	D;.;.;.
Vest4		0.94
MutPred		0.73		Loss of phosphorylation at T80 (P = 0.0528);Loss of phosphorylation at T80 (P = 0.0528);Loss of phosphorylation at T80 (P = 0.0528);Loss of phosphorylation at T80 (P = 0.0528);
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.87
gMVP		0.61

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: rs397514711; hg19: chr16-85942659; COSMIC: COSV51897805; COSMIC: COSV51897805;