dbSNP rs764597369: IRAK4:p.Ala97Glu (chr12-43771348-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_016123.4(IRAK4):c.290C>A(p.Ala97Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. A97V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

IRAK4
NM_016123.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.28

Publications

3 publications found

Variant links:

Genes affected

IRAK4 (HGNC:17967): (interleukin 1 receptor associated kinase 4) This gene encodes a kinase that activates NF-kappaB in both the Toll-like receptor (TLR) and T-cell receptor (TCR) signaling pathways. The protein is essential for most innate immune responses. Mutations in this gene result in IRAK4 deficiency and recurrent invasive pneumococcal disease. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

IRAK4 Gene-Disease associations (from GenCC):

immunodeficiency 67
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

IRAK4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.83

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016123.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IRAK4	NM_016123.4	MANE Select	c.290C>A	p.Ala97Glu	missense	Exon 3 of 12	NP_057207.2
IRAK4	NM_001114182.3		c.290C>A	p.Ala97Glu	missense	Exon 4 of 13	NP_001107654.1
IRAK4	NM_001351345.2		c.290C>A	p.Ala97Glu	missense	Exon 4 of 13	NP_001338274.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IRAK4	ENST00000613694.5	TSL:1 MANE Select	c.290C>A	p.Ala97Glu	missense	Exon 3 of 12	ENSP00000479889.3
IRAK4	ENST00000551736.5	TSL:1	c.290C>A	p.Ala97Glu	missense	Exon 4 of 13	ENSP00000446490.1
IRAK4	ENST00000547101.5	TSL:1	n.*192C>A		non_coding_transcript_exon	Exon 4 of 13	ENSP00000449317.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251314

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461798

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111968

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.072

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

-0.068

MutationAssessor

Uncertain

2.5

PhyloP100

4.3

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.41

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.014

Polyphen

1.0

Vest4

0.83

MutPred

0.51

Gain of catalytic residue at E92 (P = 0.0088)

MVP

0.91

MPC

0.26

ClinPred

0.98

GERP RS

6.2

Varity_R

0.91

gMVP

0.88

Mutation Taster

=39/61

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over