Variant 12-66189300-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 8P and 6B. PVS1BP6_ModerateBS2

The NM_007199.3(IRAK3):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,536,240 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00040 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 2 hom. )

Consequence

IRAK3
NM_007199.3 start_lost

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.80

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PVS1

Start lost variant, no new inframe start found.

BP6

Variant 12-66189300-A-G is Benign according to our data. Variant chr12-66189300-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 736195.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRAK3	NM_007199.3 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/12	ENST00000261233.9
IRAK3	NM_001142523.2 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRAK3	ENST00000261233.9 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/12	1	NM_007199.3	P1	Q9Y616-1
IRAK3	ENST00000545837.1 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/2	1
IRAK3	ENST00000457197.2 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/11	2			Q9Y616-2

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00349

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000204

AC:

AN:

132448

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

72660

show subpopulations

Gnomad AFR exome

AF:

0.000155

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00346

Gnomad NFE exome

AF:

0.000140

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000190

AC:

263

AN:

1383928

Hom.:

Cov.:

AF XY:

0.000184

AC XY:

126

AN XY:

683186

show subpopulations

Gnomad4 AFR exome

AF:

0.0000315

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000278

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00417

Gnomad4 NFE exome

AF:

0.0000954

Gnomad4 OTH exome

AF:

0.000312

GnomAD4 genome

AF:

0.000400

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00349

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000794

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.000345

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Mar 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.11

T;.;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Benign

-0.85

MutationTaster

Benign

1.0

D;D;D

PROVEAN

Benign

-1.8

N;N;N

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.12

B;B;B

Vest4

0.64

MutPred

0.98

Gain of catalytic residue at C5 (P = 0.0011);Gain of catalytic residue at C5 (P = 0.0011);Gain of catalytic residue at C5 (P = 0.0011);

MVP

0.83

ClinPred

0.40

GERP RS

3.3

Varity_R

0.95

gMVP

0.32

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over