Variant X-154014164-T-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001569.4(IRAK1):c.1417A>T(p.Ile473Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000339 in 1,207,749 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 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 0.000045 ( 0 hom., 3 hem., cov: 22)

Exomes 𝑓: 0.000033 ( 0 hom. 16 hem. )

Consequence

IRAK1
NM_001569.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.33

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=0.23986575).

BS2

High Hemizygotes in GnomAd at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRAK1	NM_001569.4 linkuse as main transcript	c.1417A>T	p.Ile473Phe	missense_variant	11/14	ENST00000369980.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRAK1	ENST00000369980.8 linkuse as main transcript	c.1417A>T	p.Ile473Phe	missense_variant	11/14	1	NM_001569.4	P1	P51617-1

Frequencies

GnomAD3 genomes

AF:

0.0000453

AC:

AN:

110281

Hom.:

Cov.:

AF XY:

0.0000922

AC XY:

AN XY:

32543

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:

0.00

Gnomad SAS

AF:

0.000389

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000570

Gnomad OTH

AF:

0.000672

GnomAD3 exomes

AF:

0.0000329

AC:

AN:

182598

Hom.:

AF XY:

0.0000743

AC XY:

AN XY:

67288

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000210

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.0000328

AC:

AN:

1097468

Hom.:

Cov.:

AF XY:

0.0000441

AC XY:

AN XY:

363012

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000924

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000249

Gnomad4 OTH exome

AF:

0.000152

GnomAD4 genome

AF:

0.0000453

AC:

AN:

110281

Hom.:

Cov.:

AF XY:

0.0000922

AC XY:

AN XY:

32543

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000389

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000570

Gnomad4 OTH

AF:

0.000672

Alfa

AF:

0.0000480

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Oct 06, 2021

The c.1417A>T (p.I473F) alteration is located in exon 11 (coding exon 11) of the IRAK1 gene. This alteration results from a A to T substitution at nucleotide position 1417, causing the isoleucine (I) at amino acid position 473 to be replaced by a phenylalanine (F). 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

0.32

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.48

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.26

T;T;.;T

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.85

T;T;T;T

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.24

T;T;T;T

MetaSVM

Uncertain

0.21

MutationAssessor

Benign

1.4

L;.;L;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.9

D;D;D;D

REVEL

Benign

0.28

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Benign

0.33

T;D;T;T

Polyphen

0.98

D;.;D;.

Vest4

0.25

MVP

0.73

MPC

1.7

ClinPred

0.35

GERP RS

4.1

Varity_R

0.64

gMVP

0.70

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

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