Variant X-154014173-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000369980.8(IRAK1):c.1408G>A(p.Ala470Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,207,574 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000014 ( 0 hom. 6 hem. )

Consequence

IRAK1
ENST00000369980.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.25

Variant links:

Genes affected

IRAK1 (HGNC:6112): (interleukin 1 receptor associated kinase 1) This gene encodes the interleukin-1 receptor-associated kinase 1, one of two putative serine/threonine kinases that become associated with the interleukin-1 receptor (IL1R) upon stimulation. This gene is partially responsible for IL1-induced upregulation of the transcription factor NF-kappa B. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

IRAK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.099016786).

BS2

High Hemizygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRAK1	NM_001569.4 linkuse as main transcript	c.1408G>A	p.Ala470Thr	missense_variant	11/14	ENST00000369980.8	NP_001560.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRAK1	ENST00000369980.8 linkuse as main transcript	c.1408G>A	p.Ala470Thr	missense_variant	11/14	1	NM_001569.4	ENSP00000358997	P1	P51617-1

Frequencies

GnomAD3 genomes

AF:

0.0000182

AC:

AN:

110133

Hom.:

Cov.:

AF XY:

0.0000309

AC XY:

AN XY:

32409

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000287

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000602

AC:

AN:

182751

Hom.:

AF XY:

0.0000742

AC XY:

AN XY:

67369

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000797

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1097441

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

362953

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000464

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000182

AC:

AN:

110133

Hom.:

Cov.:

AF XY:

0.0000309

AC XY:

AN XY:

32409

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000287

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000190

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000567

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2022

The c.1408G>A (p.A470T) alteration is located in exon 11 (coding exon 11) of the IRAK1 gene. This alteration results from a G to A substitution at nucleotide position 1408, causing the alanine (A) at amino acid position 470 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;T;.;T

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.83

T;T;T;T

M_CAP

Benign

0.025

MetaRNN

Benign

0.099

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;.;L;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-2.0

N;D;N;N

REVEL

Benign

0.21

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Benign

0.11

T;D;T;D

Polyphen

1.0

D;.;D;.

Vest4

0.17

MutPred

0.47

Gain of methylation at K475 (P = 0.0897);.;Gain of methylation at K475 (P = 0.0897);.;

MVP

0.70

MPC

1.3

ClinPred

0.20

GERP RS

4.3

Varity_R

0.27

gMVP

0.34

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

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