Variant 12-66210200-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_007199.3(IRAK3):c.435A>G(p.Lys145=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0133 in 1,596,312 control chromosomes in the GnomAD database, including 202 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 20 hom., cov: 33)

Exomes 𝑓: 0.014 ( 182 hom. )

Consequence

IRAK3
NM_007199.3 splice_region, synonymous

Scores

Splicing: ADA: 0.7558

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.79

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 Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 12-66210200-A-G is Benign according to our data. Variant chr12-66210200-A-G is described in ClinVar as [Benign]. Clinvar id is 774329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0136 (19673/1444012) while in subpopulation NFE AF= 0.0163 (17827/1096714). AF 95% confidence interval is 0.0161. There are 182 homozygotes in gnomad4_exome. There are 9692 alleles in male gnomad4_exome subpopulation. Median coverage is 26. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 20 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRAK3	NM_007199.3 linkuse as main transcript	c.435A>G	p.Lys145=	splice_region_variant, synonymous_variant	4/12	ENST00000261233.9
IRAK3	NM_001142523.2 linkuse as main transcript	c.252A>G	p.Lys84=	splice_region_variant, synonymous_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRAK3	ENST00000261233.9 linkuse as main transcript	c.435A>G	p.Lys145=	splice_region_variant, synonymous_variant	4/12	1	NM_007199.3	P1	Q9Y616-1
IRAK3	ENST00000457197.2 linkuse as main transcript	c.252A>G	p.Lys84=	splice_region_variant, synonymous_variant	3/11	2			Q9Y616-2

Frequencies

GnomAD3 genomes

AF:

0.0101

AC:

1541

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00304

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0161

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.00471

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0152

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.00962

AC:

2400

AN:

249564

Hom.:

AF XY:

0.00962

AC XY:

1297

AN XY:

134892

show subpopulations

Gnomad AFR exome

AF:

0.00268

Gnomad AMR exome

AF:

0.00935

Gnomad ASJ exome

AF:

0.00398

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00283

Gnomad FIN exome

AF:

0.00467

Gnomad NFE exome

AF:

0.0153

Gnomad OTH exome

AF:

0.0123

GnomAD4 exome

AF:

0.0136

AC:

19673

AN:

1444012

Hom.:

182

Cov.:

AF XY:

0.0135

AC XY:

9692

AN XY:

719384

show subpopulations

Gnomad4 AFR exome

AF:

0.00194

Gnomad4 AMR exome

AF:

0.00979

Gnomad4 ASJ exome

AF:

0.00443

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00222

Gnomad4 FIN exome

AF:

0.00572

Gnomad4 NFE exome

AF:

0.0163

Gnomad4 OTH exome

AF:

0.0114

GnomAD4 genome

AF:

0.0101

AC:

1540

AN:

152300

Hom.:

Cov.:

AF XY:

0.00967

AC XY:

720

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00303

Gnomad4 AMR

AF:

0.0161

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00352

Gnomad4 FIN

AF:

0.00471

Gnomad4 NFE

AF:

0.0151

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0134

Hom.:

Bravo

AF:

0.0109

Asia WGS

AF:

0.000867

AC:

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.76

dbscSNV1_RF

Benign

0.45

SpliceAI score (max)

0.060

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