dbSNP rs771773479: IRF8:p.Arg361Ser (chr16-85920201-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002163.4(IRF8):c.1081C>A(p.Arg361Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000714 in 1,400,420 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R361G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

IRF8
NM_002163.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.45

Publications

0 publications found

Variant links:

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

IRF8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF8	NM_002163.4 link	c.1081C>A	p.Arg361Ser	missense_variant	Exon 8 of 9	ENST00000268638.10	NP_002154.1	Q02556
IRF8	NM_001363907.1 link	c.1111C>A	p.Arg371Ser	missense_variant	Exon 8 of 9		NP_001350836.1
IRF8	NM_001363908.1 link	c.469C>A	p.Arg157Ser	missense_variant	Exon 6 of 7		NP_001350837.1
IRF8	XM_047434052.1 link	c.1111C>A	p.Arg371Ser	missense_variant	Exon 9 of 10		XP_047290008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF8	ENST00000268638.10 link	c.1081C>A	p.Arg361Ser	missense_variant	Exon 8 of 9	1	NM_002163.4	ENSP00000268638.4		Q02556

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.14e-7

AC:

AN:

1400420

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

698896

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32180

American (AMR)

AF:

0.00

AC:

AN:

44306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25360

East Asian (EAS)

AF:

0.00

AC:

AN:

38374

South Asian (SAS)

AF:

0.00

AC:

AN:

85296

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5566

European-Non Finnish (NFE)

AF:

9.44e-7

AC:

AN:

1059028

Other (OTH)

AF:

0.00

AC:

AN:

57956

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.73

D;T;T

Eigen

Benign

0.093

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.85

D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.42

T;T;T

MetaSVM

Uncertain

0.48

MutationAssessor

Benign

1.8

L;.;.

PhyloP100

4.4

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.9

N;N;N

REVEL

Uncertain

0.37

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.035

D;T;T

Polyphen

0.28

B;.;.

Vest4

0.56

MutPred

0.45

Gain of ubiquitination at K363 (P = 0.0747);.;.;

MVP

0.66

MPC

1.6

ClinPred

0.87

GERP RS

5.2

Varity_R

0.36

gMVP

0.33

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

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rs771773479

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over