16-85918797-T-A

Variant names:

• chr16-85918797-T-A
• rs202046728
• NM_002163.4:c.982T>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002163.4(IRF8):​c.982T>A​(p.Phe328Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F328V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IRF8 NM_002163.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.296
• Publications: 5 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=0.2712646).

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.982T>A	p.Phe328Ile	missense	Exon 7 of 9	NP_002154.1	Q02556
	IRF8	NM_001363907.1		c.1012T>A	p.Phe338Ile	missense	Exon 7 of 9	NP_001350836.1
	IRF8	NM_001363908.1		c.370T>A	p.Phe124Ile	missense	Exon 5 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.982T>A	p.Phe328Ile	missense	Exon 7 of 9	ENSP00000268638.4	Q02556
	IRF8	ENST00000564803.6	TSL:2	c.982T>A	p.Phe328Ile	missense	Exon 7 of 9	ENSP00000456992.2	Q02556
	IRF8	ENST00000696887.1		c.982T>A	p.Phe328Ile	missense	Exon 7 of 9	ENSP00000512953.1	Q02556

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000408 AC: 1 AN: 244972 AF XY: 0.00000750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455996 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724672

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.99	L
PhyloP100		0.30
PrimateAI	Benign	0.48	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.26
Sift	Benign	0.22	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.41
MutPred		0.58		Loss of disorder (P = 0.2092)
MVP		0.59
MPC		0.77
ClinPred		0.099	T
GERP RS		0.11
Varity_R		0.045
gMVP		0.39

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: rs202046728; hg19: chr16-85952403;