16-85911581-G-A

Variant names:

• chr16-85911581-G-A
• rs138854374
• NM_002163.4:c.370G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_002163.4(IRF8):​c.370G>A​(p.Val124Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000277 in 1,614,064 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V124E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: IRF8 NM_002163.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.99
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057842433).
• BP6: Variant 16-85911581-G-A is Benign according to our data. Variant chr16-85911581-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 542154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF8	NM_002163.4	MANE Select	c.370G>A	p.Val124Met	missense	Exon 4 of 9	NP_002154.1
	IRF8	NM_001363908.1		c.-137G>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 7	NP_001350837.1
	IRF8	NM_001363907.1		c.400G>A	p.Val134Met	missense	Exon 4 of 9	NP_001350836.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF8	ENST00000268638.10	TSL:1 MANE Select	c.370G>A	p.Val124Met	missense	Exon 4 of 9	ENSP00000268638.4
	IRF8	ENST00000564803.6	TSL:2	c.370G>A	p.Val124Met	missense	Exon 4 of 9	ENSP00000456992.2
	IRF8	ENST00000696887.1		c.370G>A	p.Val124Met	missense	Exon 4 of 9	ENSP00000512953.1

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 215 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00468

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000394 AC: 99 AN: 251432 AF XY: 0.000265

Gnomad AFR exome AF: 0.00461

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000158 AC: 231 AN: 1461706 Hom.: 1 Cov.: 31 AF XY: 0.000147 AC XY: 107 AN XY: 727154

African (AFR) AF: 0.00451 AC: 151 AN: 33474

American (AMR) AF: 0.000402 AC: 18 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111892

Other (OTH) AF: 0.000480 AC: 29 AN: 60386

GnomAD4 genome AF: 0.00142 AC: 216 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.00132 AC XY: 98 AN XY: 74502

African (AFR) AF: 0.00469 AC: 195 AN: 41578

American (AMR) AF: 0.000718 AC: 11 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68038

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.000610 Hom.: 1

Bravo AF: 0.00197

ESP6500AA AF: 0.00614 AC: 27

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000568 AC: 69

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Likely 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
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	0.13
DANN	Benign	0.86
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.0058	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.90	L
PhyloP100		-2.0
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.27
Sift	Benign	0.38	T
Sift4G	Benign	0.17	T
Polyphen		0.0030	B
Vest4		0.094
MVP		0.77
MPC		0.55
ClinPred		0.0022	T
GERP RS		-6.4
Varity_R		0.049
gMVP		0.13
Mutation Taster		=92/8	polymorphism

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: rs138854374; hg19: chr16-85945187; COSMIC: COSV99236605; COSMIC: COSV99236605;