NM_002163.4:c.*354C>T

Variant names:

• chr16-85921636-C-T
• rs10514611
• NM_002163.4:c.*354C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002163.4(IRF8):​c.*354C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 279,678 control chromosomes in the GnomAD database, including 6,989 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (3935 hom., cov: 33)
  • Exomes 𝑓: 0.21 (3054 hom.)
• Consequence: IRF8 NM_002163.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.506
• Publications: 20 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-85921636-C-T is Benign according to our data. Variant chr16-85921636-C-T is described in ClinVar as Benign. ClinVar VariationId is 1168174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.234 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF8	NM_002163.4	MANE Select	c.*354C>T		3_prime_UTR	Exon 9 of 9	NP_002154.1
	IRF8	NM_001363907.1		c.*354C>T		3_prime_UTR	Exon 9 of 9	NP_001350836.1
	IRF8	NM_001363908.1		c.*354C>T		3_prime_UTR	Exon 7 of 7	NP_001350837.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF8	ENST00000268638.10	TSL:1 MANE Select	c.*354C>T		3_prime_UTR	Exon 9 of 9	ENSP00000268638.4
	IRF8	ENST00000564803.6	TSL:2	c.*354C>T		3_prime_UTR	Exon 9 of 9	ENSP00000456992.2
	IRF8	ENST00000696887.1		c.*354C>T		3_prime_UTR	Exon 9 of 9	ENSP00000512953.1

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34230 AN: 152012 Hom.: 3929 Cov.: 33

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.215

GnomAD4 exome AF: 0.212 AC: 27001 AN: 127548 Hom.: 3054 Cov.: 0 AF XY: 0.205 AC XY: 13747 AN XY: 67134

African (AFR) AF: 0.235 AC: 892 AN: 3790

American (AMR) AF: 0.181 AC: 863 AN: 4762

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 663 AN: 3500

East Asian (EAS) AF: 0.211 AC: 1244 AN: 5900

South Asian (SAS) AF: 0.138 AC: 2673 AN: 19334

European-Finnish (FIN) AF: 0.305 AC: 1899 AN: 6218

Middle Eastern (MID) AF: 0.131 AC: 67 AN: 512

European-Non Finnish (NFE) AF: 0.224 AC: 17141 AN: 76606

Other (OTH) AF: 0.225 AC: 1559 AN: 6926

GnomAD4 genome AF: 0.225 AC: 34268 AN: 152130 Hom.: 3935 Cov.: 33 AF XY: 0.226 AC XY: 16770 AN XY: 74366

African (AFR) AF: 0.238 AC: 9875 AN: 41500

American (AMR) AF: 0.179 AC: 2742 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 655 AN: 3468

East Asian (EAS) AF: 0.197 AC: 1020 AN: 5184

South Asian (SAS) AF: 0.126 AC: 607 AN: 4830

European-Finnish (FIN) AF: 0.306 AC: 3225 AN: 10552

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.227 AC: 15459 AN: 67984

Other (OTH) AF: 0.220 AC: 464 AN: 2110

Alfa AF: 0.225 Hom.: 14574

Bravo AF: 0.218

Asia WGS AF: 0.176 AC: 612 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.6
DANN	Benign	0.56
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

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: rs10514611; hg19: chr16-85955242;