rs2270503

Variant names:

• chr16-85921195-G-A
• rs2270503
• NM_002163.4:c.1194G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-85921195-G-A
• chr16-85921195-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002163.4(IRF8):​c.1194G>A​(p.Pro398Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00481 in 1,614,174 control chromosomes in the GnomAD database, including 233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (211 hom.)
• Consequence: IRF8 NM_002163.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.839

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 16-85921195-G-A is Benign according to our data. Variant chr16-85921195-G-A is described in ClinVar as [Benign]. Clinvar id is 475386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.839 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.072 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF8	NM_002163.4	c.1194G>A	p.Pro398Pro	synonymous_variant	Exon 9 of 9	ENST00000268638.10	NP_002154.1
IRF8	NM_001363907.1	c.1224G>A	p.Pro408Pro	synonymous_variant	Exon 9 of 9		NP_001350836.1
IRF8	NM_001363908.1	c.582G>A	p.Pro194Pro	synonymous_variant	Exon 7 of 7		NP_001350837.1
IRF8	XM_047434052.1	c.1224G>A	p.Pro408Pro	synonymous_variant	Exon 10 of 10		XP_047290008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF8	ENST00000268638.10	c.1194G>A	p.Pro398Pro	synonymous_variant	Exon 9 of 9	1	NM_002163.4	ENSP00000268638.4

Frequencies

GnomAD3 genomes AF: 0.00742 AC: 1130 AN: 152202 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00306

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0438

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0475

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.0158 AC: 3982 AN: 251408 Hom.: 140 AF XY: 0.0134 AC XY: 1827 AN XY: 135904

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.0772

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0478

Gnomad SAS exome AF: 0.00990

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.0125

GnomAD4 exome AF: 0.00453 AC: 6624 AN: 1461854 Hom.: 211 Cov.: 31 AF XY: 0.00449 AC XY: 3263 AN XY: 727230

Gnomad4 AFR exome AF: 0.00323

Gnomad4 AMR exome AF: 0.0741

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0466

Gnomad4 SAS exome AF: 0.0101

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000719

Gnomad4 OTH exome AF: 0.00644

GnomAD4 genome AF: 0.00745 AC: 1135 AN: 152320 Hom.: 22 Cov.: 32 AF XY: 0.00820 AC XY: 611 AN XY: 74490

Gnomad4 AFR AF: 0.00310

Gnomad4 AMR AF: 0.0439

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0476

Gnomad4 SAS AF: 0.0124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00436 Hom.: 10

Bravo AF: 0.0115

Asia WGS AF: 0.0270 AC: 95 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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 23% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported. -

Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency;C4016741:Immunodeficiency 32B Benign:1

Feb 03, 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.0
DANN	Benign	0.51

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: rs2270503; hg19: chr16-85954801;