chr16-85902783-T-TGGTGGCTGCA

Variant names:

• chr16-85902783-T-TGGTGGCTGCA
• rs29001489
• ENST00000563180.1:c.-229_-220dupGGCTGCAGGT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_002163.4(IRF8):​c.-1-228_-1-219dupGGCTGCAGGT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.62 (31791 hom., cov: 0)
  • Exomes 𝑓: 0.51 (58536 hom.)
• Consequence: IRF8 NM_002163.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.310
• Publications: 0 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 -10 ACMG points.

• BP6: Variant 16-85902783-T-TGGTGGCTGCA is Benign according to our data. Variant chr16-85902783-T-TGGTGGCTGCA is described in ClinVar as [Benign]. Clinvar id is 2688522.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.888 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF8	NM_002163.4	c.-1-228_-1-219dupGGCTGCAGGT		intron_variant	Intron 1 of 8	ENST00000268638.10	NP_002154.1
IRF8	XM_047434052.1	c.-74_-65dupGGCTGCAGGT		5_prime_UTR_variant	Exon 2 of 10		XP_047290008.1
IRF8	NM_001363907.1	c.-78_-77insGGTGGCTGCA		upstream_gene_variant			NP_001350836.1
IRF8	NM_001363908.1	c.-739_-738insGGTGGCTGCA		upstream_gene_variant			NP_001350837.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF8	ENST00000268638.10	c.-1-228_-1-219dupGGCTGCAGGT		intron_variant	Intron 1 of 8	1	NM_002163.4	ENSP00000268638.4

Frequencies

GnomAD3 genomes AF: 0.616 AC: 93338 AN: 151412 Hom.: 31717 Cov.: 0

Gnomad AFR AF: 0.895

Gnomad AMI AF: 0.506

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.496

Gnomad EAS AF: 0.837

Gnomad SAS AF: 0.528

Gnomad FIN AF: 0.516

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.449

Gnomad OTH AF: 0.598

GnomAD4 exome AF: 0.511 AC: 212330 AN: 415618 Hom.: 58536 Cov.: 3 AF XY: 0.507 AC XY: 112274 AN XY: 221320

African (AFR) AF: 0.894 AC: 10573 AN: 11826

American (AMR) AF: 0.712 AC: 14956 AN: 21020

Ashkenazi Jewish (ASJ) AF: 0.485 AC: 6346 AN: 13094

East Asian (EAS) AF: 0.816 AC: 21701 AN: 26596

South Asian (SAS) AF: 0.514 AC: 24153 AN: 47034

European-Finnish (FIN) AF: 0.492 AC: 11918 AN: 24230

Middle Eastern (MID) AF: 0.517 AC: 931 AN: 1800

European-Non Finnish (NFE) AF: 0.443 AC: 109046 AN: 246328

Other (OTH) AF: 0.536 AC: 12706 AN: 23690

GnomAD4 genome AF: 0.617 AC: 93474 AN: 151532 Hom.: 31791 Cov.: 0 AF XY: 0.621 AC XY: 45981 AN XY: 74054

African (AFR) AF: 0.896 AC: 36995 AN: 41302

American (AMR) AF: 0.669 AC: 10193 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 1716 AN: 3458

East Asian (EAS) AF: 0.836 AC: 4298 AN: 5140

South Asian (SAS) AF: 0.528 AC: 2529 AN: 4788

European-Finnish (FIN) AF: 0.516 AC: 5446 AN: 10550

Middle Eastern (MID) AF: 0.493 AC: 144 AN: 292

European-Non Finnish (NFE) AF: 0.449 AC: 30442 AN: 67786

Other (OTH) AF: 0.602 AC: 1259 AN: 2090

Alfa AF: 0.312 Hom.: 451

Asia WGS AF: 0.725 AC: 2517 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 91% of patients studied by a panel of primary immunodeficiencies. Number of patients: 80. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.31
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs29001489; hg19: chr16-85936389; COSMIC: COSV107276108; COSMIC: COSV107276108;