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. 16/23 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
• Publications: 12 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]

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 VariationId is 475393.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR,AD gene

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.602C>T	p.Ala201Val	missense splice_region	Exon 7 of 9	NP_002154.1
	IRF8	NM_001363907.1		c.632C>T	p.Ala211Val	missense splice_region	Exon 7 of 9	NP_001350836.1
	IRF8	NM_001363908.1		c.-11C>T		splice_region	Exon 5 of 7	NP_001350837.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF8	ENST00000268638.10	TSL:1 MANE Select	c.602C>T	p.Ala201Val	missense splice_region	Exon 7 of 9	ENSP00000268638.4
	IRF8	ENST00000564803.6	TSL:2	c.602C>T	p.Ala201Val	missense splice_region	Exon 7 of 9	ENSP00000456992.2
	IRF8	ENST00000696887.1		c.602C>T	p.Ala201Val	missense splice_region	Exon 7 of 9	ENSP00000512953.1

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

African (AFR) AF: 0.000540 AC: 18 AN: 33354

American (AMR) AF: 0.00436 AC: 194 AN: 44488

Ashkenazi Jewish (ASJ) AF: 0.00381 AC: 99 AN: 25962

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.000455 AC: 39 AN: 85708

European-Finnish (FIN) AF: 0.00353 AC: 138 AN: 39072

Middle Eastern (MID) AF: 0.000726 AC: 3 AN: 4132

European-Non Finnish (NFE) AF: 0.00422 AC: 4688 AN: 1110426

Other (OTH) 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

African (AFR) AF: 0.000529 AC: 22 AN: 41594

American (AMR) AF: 0.00555 AC: 85 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.00424 AC: 45 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00412 AC: 280 AN: 68036

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency;C4751209:Immunodeficiency 32B (3)
1	-	1	Immunodeficiency 32B (2)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0081	T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.55
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.31
Sift	Benign	0.19	T
Sift4G	Benign	0.62	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

Other links and lift over

dbSNP: rs144424711; hg19: chr16-85952023;