rs144424711

Variant names:

• chr16-85918417-C-T
• rs144424711
• NM_002163.4:c.602C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002163.4(IRF8):​c.602C>T​(p.Ala201Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00365 in 1,595,148 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A201A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (14 hom.)
• Consequence: IRF8 NM_002163.4 missense, splice_region
• Scores: Splicing: ADA: 0.00002584
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:3
• Conservation: PhyloP100: 0.549

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]

MIR6774 (HGNC:50202): (microRNA 6774) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008142531).
• BP6: Variant 16-85918417-C-T is Benign according to our data. Variant chr16-85918417-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475393.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=3}.
• BS2: High AC in GnomAd4 at 455 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF8	NM_002163.4	c.602C>T	p.Ala201Val	missense_variant, splice_region_variant	Exon 7 of 9	ENST00000268638.10	NP_002154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF8	ENST00000268638.10	c.602C>T	p.Ala201Val	missense_variant, splice_region_variant	Exon 7 of 9	1	NM_002163.4	ENSP00000268638.4

Frequencies

GnomAD3 genomes AF: 0.00299 AC: 455 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000530

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00411

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00276 AC: 644 AN: 233516 AF XY: 0.00273

Gnomad AFR exome AF: 0.000518

Gnomad AMR exome AF: 0.00384

Gnomad ASJ exome AF: 0.00398

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00425

Gnomad NFE exome AF: 0.00353

Gnomad OTH exome AF: 0.00322

GnomAD4 exome AF: 0.00372 AC: 5361 AN: 1442788 Hom.: 14 Cov.: 31 AF XY: 0.00363 AC XY: 2606 AN XY: 717876

Gnomad4 AFR exome AF: 0.000540 AC: 18 AN: 33354

Gnomad4 AMR exome AF: 0.00436 AC: 194 AN: 44488

Gnomad4 ASJ exome AF: 0.00381 AC: 99 AN: 25962

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39640

Gnomad4 SAS exome AF: 0.000455 AC: 39 AN: 85708

Gnomad4 FIN exome AF: 0.00353 AC: 138 AN: 39072

Gnomad4 NFE exome AF: 0.00422 AC: 4688 AN: 1110426

Gnomad4 Remaining exome AF: 0.00303 AC: 182 AN: 60006

GnomAD4 genome AF: 0.00299 AC: 455 AN: 152360 Hom.: 0 Cov.: 33 AF XY: 0.00286 AC XY: 213 AN XY: 74500

Gnomad4 AFR AF: 0.000529 AC: 0.000528922 AN: 0.000528922

Gnomad4 AMR AF: 0.00555 AC: 0.00555265 AN: 0.00555265

Gnomad4 ASJ AF: 0.00374 AC: 0.00374424 AN: 0.00374424

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000621 AC: 0.000620604 AN: 0.000620604

Gnomad4 FIN AF: 0.00424 AC: 0.00423729 AN: 0.00423729

Gnomad4 NFE AF: 0.00412 AC: 0.00411547 AN: 0.00411547

Gnomad4 OTH AF: 0.00331 AC: 0.00331126 AN: 0.00331126

Alfa AF: 0.00339 Hom.: 2

Bravo AF: 0.00323

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000911 AC: 4

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00240 AC: 290

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00633

EpiControl AF: 0.00409

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency;C4751209:Immunodeficiency 32B Uncertain:2 Benign:1

Oct 26, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Immunodeficiency 32B Pathogenic:1 Benign:1

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in IRF8 is predicted to replace alanine with valine at codon 201, p.(Ala201Val). There is a moderate (60-100) physicochemical difference between alanine and valine. The highest population minor allele frequency is in the Latino/Admixed American population with allele frequency of 0.33% (rs144424711, 131/35004 alleles, 1 homozygotes in gnomAD v2.1). Computational evidence is uninformative for the missense substitution (REVEL = 0.306). This variant has been reported in an individual with NK cell deficiency (PMID: 27893462). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.2.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1, BP4, PP4 -

Jun 08, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified Uncertain:1

Mar 05, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: IRF8 c.602C>T (p.Ala201Val) results in a non-conservative amino acid change located in the IRF association domain (Mace 2017) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0026 in 264914 control chromosomes in the gnomAD database, including 2 homozygotes. c.602C>T has been reported in the literature in a compound heterozygous individual (together with c.671C>T (p.Pro224Leu)) affected with Immunodeficiency 32B (Mace 2017). This genotype was not confirmed in the affected sister and other family members who carried either variant in heterozygosity were unaffected; although the observed phenotypes in this family could be consistent with an autosomal recessive inheritance mode, the available data are not sufficient to confirm the role of the variant of interest in association with the disease. The variant was also reported in heterozygous state in two unrelated individuals with pulmonary nontuberculous mycobacterial disease (PNTM) (Mace 2017, Szymanski 2015). These reports therefore do not provide unequivocal conclusion about the association of the variant with Immunodeficiency 32B. One of these studies also reported experimental evidence and demonstrated decreased NK cell number and function, with interrupted NK cell maturation in the compound heterozygous patient, but normal NK cell number and cytotoxic function in the heterozygous carriers (Mace 2017). These data, however, do not allow convincing conclusion about the variant effect. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Benign:1

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IRF8: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	11
DANN	Benign	0.89
DEOGEN2	Benign	0.35	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.74	T;T
MetaRNN	Benign	0.0081	T;T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	1.0	L;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.31
Sift	Benign	0.19	T;T
Sift4G	Benign	0.62	T;T
Polyphen		0.0	B;.
Vest4		0.26
MVP		0.65
MPC		0.55
ClinPred		0.00066	T
GERP RS		-0.74
Varity_R		0.038
gMVP		0.60
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.028
SpliceAI score (max)		0.010		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: rs144424711; hg19: chr16-85952023;