dbSNP rs141209982: IRAK4:p.Thr177Ala (chr12-43772950-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_016123.4(IRAK4):c.529A>G(p.Thr177Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000537 in 1,610,808 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00055 ( 1 hom. )

Consequence

IRAK4
NM_016123.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 8.17

Publications

6 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.897

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	UniProt
IRAK4	NM_016123.4	MANE Select	c.529A>G	p.Thr177Ala	missense	Exon 5 of 12	NP_057207.2	Q9NWZ3-1
IRAK4	NM_001114182.3		c.529A>G	p.Thr177Ala	missense	Exon 6 of 13	NP_001107654.1	Q9NWZ3-1
IRAK4	NM_001351345.2		c.529A>G	p.Thr177Ala	missense	Exon 6 of 13	NP_001338274.1	Q69FE3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IRAK4	ENST00000613694.5	TSL:1 MANE Select	c.529A>G	p.Thr177Ala	missense	Exon 5 of 12	ENSP00000479889.3	Q9NWZ3-1
IRAK4	ENST00000551736.5	TSL:1	c.529A>G	p.Thr177Ala	missense	Exon 6 of 13	ENSP00000446490.1	Q9NWZ3-1
IRAK4	ENST00000547101.5	TSL:1	n.*431A>G		non_coding_transcript_exon	Exon 6 of 13	ENSP00000449317.1	F8VW24

Frequencies

GnomAD3 genomes

AF:

0.000414

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000347

AC:

AN:

251044

AF XY:

0.000346

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000502

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000550

AC:

802

AN:

1458538

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

400

AN XY:

725442

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33442

American (AMR)

AF:

0.000492

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.000192

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39572

South Asian (SAS)

AF:

0.000187

AC:

AN:

85392

European-Finnish (FIN)

AF:

0.0000376

AC:

AN:

53224

Middle Eastern (MID)

AF:

0.000349

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.000649

AC:

721

AN:

1110144

Other (OTH)

AF:

0.000531

AC:

AN:

60254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

111

148

185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000414

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41578

American (AMR)

AF:

0.000458

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000691

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000396

Hom.:

Bravo

AF:

0.000427

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000305

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3474

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Immunodeficiency 67 (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.90

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.7

PhyloP100

8.2

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.97

Vest4

0.89

MVP

0.97

MPC

0.091

ClinPred

0.51

GERP RS

5.2

Varity_R

0.87

gMVP

0.82

Mutation Taster

=33/67

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over