Genetic Variant NM_007199.3:c.109G>T (chr12-66189408-G-T) – 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_007199.3(IRAK3):c.109G>T(p.Gly37Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000779 in 1,283,074 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. G37R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.8e-7 ( 0 hom. )

Consequence

IRAK3
NM_007199.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.40

Publications

0 publications found

Variant links:

Genes affected

IRAK3 (HGNC:17020): (interleukin 1 receptor associated kinase 3) This gene encodes a member of the interleukin-1 receptor-associated kinase protein family. Members of this family are essential components of the Toll/IL-R immune signal transduction pathways. This protein is primarily expressed in monocytes and macrophages and functions as a negative regulator of Toll-like receptor signaling. Mutations in this gene are associated with a susceptibility to asthma. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

IRAK3 Gene-Disease associations (from GenCC):

asthma-related traits, susceptibility to, 5
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

IRAK3 links:

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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
IRAK3	NM_007199.3 link	c.109G>T	p.Gly37Cys	missense_variant	Exon 1 of 12	ENST00000261233.9	NP_009130.2	Q9Y616-1
IRAK3	NM_001142523.2 link	c.109G>T	p.Gly37Cys	missense_variant	Exon 1 of 11		NP_001135995.1	Q9Y616-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IRAK3	ENST00000261233.9 link	c.109G>T	p.Gly37Cys	missense_variant	Exon 1 of 12	1	NM_007199.3	ENSP00000261233.4	Q9Y616-1
IRAK3	ENST00000545837.1 link	c.109G>T	p.Gly37Cys	missense_variant	Exon 1 of 2	1		ENSP00000441321.1	F5GYN6
IRAK3	ENST00000457197.2 link	c.109G>T	p.Gly37Cys	missense_variant	Exon 1 of 11	2		ENSP00000409852.2	Q9Y616-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.79e-7

AC:

AN:

1283074

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

626642

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25790

American (AMR)

AF:

0.00

AC:

AN:

24694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21766

East Asian (EAS)

AF:

0.00

AC:

AN:

28238

South Asian (SAS)

AF:

0.00

AC:

AN:

68848

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31864

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3766

European-Non Finnish (NFE)

AF:

9.75e-7

AC:

AN:

1025228

Other (OTH)

AF:

0.00

AC:

AN:

52880

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Pathogenic

0.57

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

T;.;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.80

T;T;T

M_CAP

Pathogenic

0.73

MetaRNN

Uncertain

0.69

D;D;D

MetaSVM

Uncertain

-0.28

MutationAssessor

Benign

1.7

L;.;L

PhyloP100

3.4

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-2.2

N;D;D

REVEL

Uncertain

0.52

Sift

Benign

0.035

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.37

MutPred

0.52

Gain of catalytic residue at L39 (P = 0);Gain of catalytic residue at L39 (P = 0);Gain of catalytic residue at L39 (P = 0);

MVP

0.97

MPC

0.19

ClinPred

0.96

GERP RS

3.4

PromoterAI

0.12

Neutral

(source)

Varity_R

0.28

gMVP

0.43

Mutation Taster

=59/41

polymorphism

(source)

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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NM_007199.3:c.109G>T

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