Variant X-154013301-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001569.4(IRAK1):c.1672G>A(p.Ala558Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000232 in 1,208,613 control chromosomes in the GnomAD database, including 1 homozygotes. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000097 ( 0 hom., 5 hem., cov: 26)

Exomes 𝑓: 0.000016 ( 1 hom. 6 hem. )

Consequence

IRAK1
NM_001569.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.504

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:

IRAK1 (HGNC:):

IRAK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.057730705).

BS2

High Hemizygotes in GnomAd4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRAK1	NM_001569.4 linkuse as main transcript	c.1672G>A	p.Ala558Thr	missense_variant	12/14	ENST00000369980.8	NP_001560.2	P51617-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRAK1	ENST00000369980.8 linkuse as main transcript	c.1672G>A	p.Ala558Thr	missense_variant	12/14	1	NM_001569.4	ENSP00000358997.3		P51617-1

Frequencies

GnomAD3 genomes

AF:

0.0000968

AC:

AN:

113585

Hom.:

Cov.:

AF XY:

0.000140

AC XY:

AN XY:

35715

show subpopulations

Gnomad AFR

AF:

0.000160

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00166

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000700

AC:

AN:

171450

Hom.:

AF XY:

0.0000482

AC XY:

AN XY:

62208

show subpopulations

Gnomad AFR exome

AF:

0.0000859

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000751

Gnomad SAS exome

AF:

0.0000538

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000155

AC:

AN:

1094976

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

361292

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000331

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000870

GnomAD4 genome

AF:

0.0000968

AC:

AN:

113637

Hom.:

Cov.:

AF XY:

0.000140

AC XY:

AN XY:

35777

show subpopulations

Gnomad4 AFR

AF:

0.000159

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00167

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000831

ExAC

AF:

0.0000496

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

Nov 28, 2023

The c.1672G>A (p.A558T) alteration is located in exon 12 (coding exon 12) of the IRAK1 gene. This alteration results from a G to A substitution at nucleotide position 1672, causing the alanine (A) at amino acid position 558 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

0.071

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.58

CADD

Benign

7.5

DANN

Benign

0.29

DEOGEN2

Benign

0.094

T;.;.;T

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.78

T;T;T;T

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.058

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;.;.;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.0

N;N;N;N

REVEL

Benign

0.085

Sift

Benign

0.40

T;T;T;T

Sift4G

Benign

0.58

T;T;T;T

Polyphen

0.014

B;B;B;.

Vest4

0.037

MVP

0.59

MPC

0.47

ClinPred

0.40

GERP RS

1.8

Varity_R

0.072

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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