chr16-85918487-C-T

Variant names:

• chr16-85918487-C-T
• rs57770209
• NM_002163.4:c.672C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002163.4(IRF8):​c.672C>T​(p.Pro224Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00334 in 1,591,368 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P224P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.017 (61 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (71 hom.)
• Consequence: IRF8 NM_002163.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.97
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068588853).
• BP6: Variant 16-85918487-C-T is Benign according to our data. Variant chr16-85918487-C-T is described in ClinVar as Benign. ClinVar VariationId is 475392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.97 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0577 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF8	NM_002163.4	MANE Select	c.672C>T	p.Pro224Pro	synonymous	Exon 7 of 9	NP_002154.1
	IRF8	NM_001363907.1		c.702C>T	p.Pro234Pro	synonymous	Exon 7 of 9	NP_001350836.1
	IRF8	NM_001363908.1		c.60C>T	p.Pro20Pro	synonymous	Exon 5 of 7	NP_001350837.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF8	ENST00000268638.10	TSL:1 MANE Select	c.672C>T	p.Pro224Pro	synonymous	Exon 7 of 9	ENSP00000268638.4
	IRF8	ENST00000564803.6	TSL:2	c.672C>T	p.Pro224Pro	synonymous	Exon 7 of 9	ENSP00000456992.2
	IRF8	ENST00000696887.1		c.672C>T	p.Pro224Pro	synonymous	Exon 7 of 9	ENSP00000512953.1

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2618 AN: 152224 Hom.: 62 Cov.: 33

Gnomad AFR AF: 0.0597

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00456 AC: 1050 AN: 230362 AF XY: 0.00333

Gnomad AFR exome AF: 0.0638

Gnomad AMR exome AF: 0.00232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000227

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000857

GnomAD4 exome AF: 0.00188 AC: 2699 AN: 1439026 Hom.: 71 Cov.: 31 AF XY: 0.00162 AC XY: 1158 AN XY: 714980

African (AFR) AF: 0.0659 AC: 2191 AN: 33226

American (AMR) AF: 0.00293 AC: 130 AN: 44380

Ashkenazi Jewish (ASJ) AF: 0.0000779 AC: 2 AN: 25664

East Asian (EAS) AF: 0.0000759 AC: 3 AN: 39506

South Asian (SAS) AF: 0.000141 AC: 12 AN: 85052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40426

Middle Eastern (MID) AF: 0.00346 AC: 15 AN: 4338

European-Non Finnish (NFE) AF: 0.0000886 AC: 98 AN: 1106718

Other (OTH) AF: 0.00415 AC: 248 AN: 59716

GnomAD4 genome AF: 0.0172 AC: 2621 AN: 152342 Hom.: 61 Cov.: 33 AF XY: 0.0167 AC XY: 1245 AN XY: 74500

African (AFR) AF: 0.0596 AC: 2479 AN: 41564

American (AMR) AF: 0.00582 AC: 89 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68042

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.00207 Hom.: 0

Bravo AF: 0.0197

ESP6500AA AF: 0.0567 AC: 247

ESP6500EA AF: 0.000471 AC: 4

ExAC AF: 0.00537 AC: 647

Asia WGS AF: 0.00549 AC: 20 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency;C4751209:Immunodeficiency 32B Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	7.4
DANN	Benign	0.74
FATHMM_MKL	Benign	0.17	N
MetaRNN	Benign	0.0069	T
PhyloP100		-3.0
PROVEAN	Pathogenic	-10	D
MVP		0.72
GERP RS		-0.95
Mutation Taster		=100/0	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: rs57770209; hg19: chr16-85952093;