rs142267779

Variant names:

• chr16-85918539-T-C
• rs142267779
• NM_002163.4:c.724T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002163.4(IRF8):​c.724T>C​(p.Tyr242His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00309 in 1,602,264 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (9 hom.)
• Consequence: IRF8 NM_002163.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.01
• Publications: 8 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]

MIR6774 (HGNC:50202): (microRNA 6774) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.032372504).
• BP6: Variant 16-85918539-T-C is Benign according to our data. Variant chr16-85918539-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 542152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 9 AD,AR gene

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.724T>C	p.Tyr242His	missense	Exon 7 of 9	NP_002154.1	Q02556
	IRF8	NM_001363907.1		c.754T>C	p.Tyr252His	missense	Exon 7 of 9	NP_001350836.1
	IRF8	NM_001363908.1		c.112T>C	p.Tyr38His	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.724T>C	p.Tyr242His	missense	Exon 7 of 9	ENSP00000268638.4	Q02556
	IRF8	ENST00000564803.6	TSL:2	c.724T>C	p.Tyr242His	missense	Exon 7 of 9	ENSP00000456992.2	Q02556
	IRF8	ENST00000696887.1		c.724T>C	p.Tyr242His	missense	Exon 7 of 9	ENSP00000512953.1	Q02556

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 291 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00368

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00188 AC: 445 AN: 236408 AF XY: 0.00186

Gnomad AFR exome AF: 0.000202

Gnomad AMR exome AF: 0.000524

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00121

Gnomad NFE exome AF: 0.00366

Gnomad OTH exome AF: 0.00152

GnomAD4 exome AF: 0.00321 AC: 4658 AN: 1449932 Hom.: 9 Cov.: 31 AF XY: 0.00318 AC XY: 2293 AN XY: 721566

African (AFR) AF: 0.000359 AC: 12 AN: 33384

American (AMR) AF: 0.000381 AC: 17 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86070

European-Finnish (FIN) AF: 0.00117 AC: 52 AN: 44396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4794

European-Non Finnish (NFE) AF: 0.00402 AC: 4471 AN: 1110882

Other (OTH) AF: 0.00175 AC: 105 AN: 60120

GnomAD4 genome AF: 0.00191 AC: 291 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.00175 AC XY: 130 AN XY: 74494

African (AFR) AF: 0.000505 AC: 21 AN: 41582

American (AMR) AF: 0.000849 AC: 13 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00368 AC: 250 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00200 Hom.: 0

Bravo AF: 0.00168

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000459 AC: 2

ESP6500EA AF: 0.00398 AC: 34

ExAC AF: 0.00186 AC: 223

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00344

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	IRF8-related disorder (1)
-	-	1	Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency;C4751209:Immunodeficiency 32B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.060
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.032	T
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.53
Sift	Benign	0.033	D
Sift4G	Benign	0.097	T
Polyphen		0.98	D
Vest4		0.50
MVP		0.91
MPC		1.4
ClinPred		0.64	D
GERP RS		5.0
Varity_R		0.21
gMVP		0.68
Mutation Taster		=88/12	polymorphism

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: rs142267779; hg19: chr16-85952145; COSMIC: COSV99076836; COSMIC: COSV99076836;