rs138854374

chr16-85911581-G-Achr16-85911581-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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. 16/21 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, single submitter B:1
• Conservation: PhyloP100: -1.99

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 -10 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 id is 542154.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 215 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF8	NM_002163.4	c.370G>A	p.Val124Met	missense_variant	4/9	ENST00000268638.10
IRF8	NM_001363907.1	c.400G>A	p.Val134Met	missense_variant	4/9
IRF8	XM_047434052.1	c.400G>A	p.Val134Met	missense_variant	5/10
IRF8	NM_001363908.1	c.-137G>A		5_prime_UTR_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF8	ENST00000268638.10	c.370G>A	p.Val124Met	missense_variant	4/9	1	NM_002163.4	P1

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

GnomAD3 exomes AF: 0.000394 AC: 99 AN: 251432 Hom.: 0 AF XY: 0.000265 AC XY: 36 AN XY: 135914

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.00451

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.000480

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

Gnomad4 AFR AF: 0.00469

Gnomad4 AMR AF: 0.000718

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000228 Hom.: 0

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

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

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;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.57	T;T;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.0058	T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.90	L;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.12	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.38	T;T;T
Sift4G	Benign	0.17	T;T;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

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