rs142267779

chr16-85918539-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002163.4(IRF8):c.724T>C(p.Tyr242His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00309 in 1,602,264 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (9 hom.)
• Consequence: IRF8 NM_002163.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.01

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.032372504).
• BP6: Variant 16-85918539-T-C is Benign according to our data. Variant chr16-85918539-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 542152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-85918539-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 291 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF8	NM_002163.4	c.724T>C	p.Tyr242His	missense_variant	7/9	ENST00000268638.10
IRF8	NM_001363907.1	c.754T>C	p.Tyr252His	missense_variant	7/9
IRF8	NM_001363908.1	c.112T>C	p.Tyr38His	missense_variant	5/7
IRF8	XM_047434052.1	c.754T>C	p.Tyr252His	missense_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF8	ENST00000268638.10	c.724T>C	p.Tyr242His	missense_variant	7/9	1	NM_002163.4	P1

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 291 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00368

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00188 AC: 445 AN: 236408 Hom.: 2 AF XY: 0.00186 AC XY: 242 AN XY: 129950

Gnomad AFR exome AF: 0.000202

Gnomad AMR exome AF: 0.000524

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00121

Gnomad NFE exome AF: 0.00366

Gnomad OTH exome AF: 0.00152

GnomAD4 exome AF: 0.00321 AC: 4658 AN: 1449932 Hom.: 9 Cov.: 31 AF XY: 0.00318 AC XY: 2293 AN XY: 721566

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.000381

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00117

Gnomad4 NFE exome AF: 0.00402

Gnomad4 OTH exome AF: 0.00175

GnomAD4 genome AF: 0.00191 AC: 291 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.00175 AC XY: 130 AN XY: 74494

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.00368

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00200 Hom.: 0

Bravo AF: 0.00168

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000459 AC: 2

ESP6500EA AF: 0.00398 AC: 34

ExAC AF: 0.00186 AC: 223

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00344

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	IRF8: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.060
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D;D;D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.032	T;T;T;T
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.1	M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.8	D;D;D;D
REVEL	Uncertain	0.53
Sift	Benign	0.033	D;D;D;D
Sift4G	Benign	0.097	T;T;D;T
Polyphen		0.98	D;.;.;.
Vest4		0.50
MVP		0.91
MPC		1.4
ClinPred		0.64	D
GERP RS		5.0
Varity_R		0.21
gMVP		0.68

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: rs142267779; hg19: chr16-85952145; COSMIC: COSV99076836; COSMIC: COSV99076836;