Variant X-154012537-G-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.2072C>T(p.Ser691Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000513 in 1,208,273 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., 6 hem., cov: 25)

Exomes 𝑓: 0.000037 ( 0 hom. 7 hem. )

Consequence

IRAK1
NM_001569.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.97

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=0.08743301).

BS2

High Hemizygotes in GnomAd at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRAK1	NM_001569.4 linkuse as main transcript	c.2072C>T	p.Ser691Phe	missense_variant	13/14	ENST00000369980.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRAK1	ENST00000369980.8 linkuse as main transcript	c.2072C>T	p.Ser691Phe	missense_variant	13/14	1	NM_001569.4	P1	P51617-1

Frequencies

GnomAD3 genomes

AF:

0.000186

AC:

AN:

113116

Hom.:

Cov.:

AF XY:

0.000170

AC XY:

AN XY:

35250

show subpopulations

Gnomad AFR

AF:

0.000577

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000375

Gnomad OTH

AF:

0.000654

GnomAD3 exomes

AF:

0.0000622

AC:

AN:

176866

Hom.:

AF XY:

0.0000320

AC XY:

AN XY:

62476

show subpopulations

Gnomad AFR exome

AF:

0.000462

Gnomad AMR exome

AF:

0.0000744

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000384

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000374

AC:

AN:

1095157

Hom.:

Cov.:

AF XY:

0.0000194

AC XY:

AN XY:

361141

show subpopulations

Gnomad4 AFR exome

AF:

0.000797

Gnomad4 AMR exome

AF:

0.0000571

Gnomad4 ASJ exome

AF:

0.0000521

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000500

Gnomad4 NFE exome

AF:

0.0000107

Gnomad4 OTH exome

AF:

0.000131

GnomAD4 genome

AF:

0.000186

AC:

AN:

113116

Hom.:

Cov.:

AF XY:

0.000170

AC XY:

AN XY:

35250

show subpopulations

Gnomad4 AFR

AF:

0.000577

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000375

Gnomad4 OTH

AF:

0.000654

Bravo

AF:

0.000204

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

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

Jan 20, 2023

The c.2072C>T (p.S691F) alteration is located in exon 13 (coding exon 13) of the IRAK1 gene. This alteration results from a C to T substitution at nucleotide position 2072, causing the serine (S) at amino acid position 691 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

0.10

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.68

Cadd

Benign

Dann

Benign

0.71

DEOGEN2

Benign

0.021

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.28

M_CAP

Benign

0.013

MetaRNN

Benign

0.087

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.96

N;N;N;N;N

PROVEAN

Benign

-1.1

REVEL

Benign

0.036

Sift

Benign

0.16

Sift4G

Benign

0.40

MVP

0.49

ClinPred

0.024

GERP RS

3.9

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