rs10514611

Positions:

• chr16-85921636-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRF8	NM_002163.4	c.*354C>T		3_prime_UTR_variant	9/9	ENST00000268638.10	NP_002154.1
IRF8	NM_001363907.1	c.*354C>T		3_prime_UTR_variant	9/9		NP_001350836.1
IRF8	NM_001363908.1	c.*354C>T		3_prime_UTR_variant	7/7		NP_001350837.1
IRF8	XM_047434052.1	c.*354C>T		3_prime_UTR_variant	10/10		XP_047290008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRF8	ENST00000268638.10	c.*354C>T		3_prime_UTR_variant	9/9	1	NM_002163.4	ENSP00000268638	P1

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

Gnomad4 AFR exome AF: 0.235

Gnomad4 AMR exome AF: 0.181

Gnomad4 ASJ exome AF: 0.189

Gnomad4 EAS exome AF: 0.211

Gnomad4 SAS exome AF: 0.138

Gnomad4 FIN exome AF: 0.305

Gnomad4 NFE exome AF: 0.224

Gnomad4 OTH exome AF: 0.225

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

Gnomad4 AFR AF: 0.238

Gnomad4 AMR AF: 0.179

Gnomad4 ASJ AF: 0.189

Gnomad4 EAS AF: 0.197

Gnomad4 SAS AF: 0.126

Gnomad4 FIN AF: 0.306

Gnomad4 NFE AF: 0.227

Gnomad4 OTH AF: 0.220

Alfa AF: 0.221 Hom.: 6360

Bravo AF: 0.218

Asia WGS AF: 0.176 AC: 612 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;C4016741:Immunodeficiency 32B Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.6
DANN	Benign	0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs10514611; hg19: chr16-85955242;