rs36085113

chr16-85920150-G-Achr16-85920150-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002163.4(IRF8):c.1030G>A(p.Gly344Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,614,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G344C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: IRF8 NM_002163.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030983895).
• BS2: High AC in GnomAd at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF8	NM_002163.4	c.1030G>A	p.Gly344Ser	missense_variant	8/9	ENST00000268638.10
IRF8	NM_001363907.1	c.1060G>A	p.Gly354Ser	missense_variant	8/9
IRF8	NM_001363908.1	c.418G>A	p.Gly140Ser	missense_variant	6/7
IRF8	XM_047434052.1	c.1060G>A	p.Gly354Ser	missense_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF8	ENST00000268638.10	c.1030G>A	p.Gly344Ser	missense_variant	8/9	1	NM_002163.4	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000756 AC: 19 AN: 251382 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135892

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 48 AN: 1461862 Hom.: 0 Cov.: 33 AF XY: 0.0000371 AC XY: 27 AN XY: 727238

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74408

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000136 Hom.: 0

Bravo AF: 0.000249

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000123 AC: 15

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

Jan 28, 2023

This variant is present in population databases (rs36085113, gnomAD 0.07%). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt IRF8 protein function. ClinVar contains an entry for this variant (Variation ID: 542145). This variant has not been reported in the literature in individuals affected with IRF8-related conditions. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 344 of the IRF8 protein (p.Gly344Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	6.0
Dann	Benign	0.67
DEOGEN2	Uncertain	0.50	T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.031	T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	-2.1	N;.;.
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.4	N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.40	T;T;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.34
MVP		0.68
MPC		0.54
ClinPred		0.0067	T
GERP RS		0.15
Varity_R		0.040
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs36085113; hg19: chr16-85953756;