NM_001569.4:c.1874C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001569.4(IRAK1):c.1874C>T(p.Thr625Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00642 in 1,208,900 control chromosomes in the GnomAD database, including 22 homozygotes. There are 2,430 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 Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0041 ( 2 hom., 122 hem., cov: 26)

Exomes 𝑓: 0.0067 ( 20 hom. 2308 hem. )

Consequence

IRAK1
NM_001569.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.425

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0053812265).

BP6

Variant X-154013099-G-A is Benign according to our data. Variant chrX-154013099-G-A is described in ClinVar as [Benign]. Clinvar id is 787610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154013099-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAK1	NM_001569.4 link	c.1874C>T	p.Thr625Met	missense_variant	Exon 12 of 14	ENST00000369980.8	NP_001560.2	P51617-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRAK1	ENST00000369980.8 link	c.1874C>T	p.Thr625Met	missense_variant	Exon 12 of 14	1	NM_001569.4	ENSP00000358997.3		P51617-1

Frequencies

GnomAD3 genomes

AF:

0.00413

AC:

468

AN:

113379

Hom.:

Cov.:

AF XY:

0.00343

AC XY:

122

AN XY:

35535

show subpopulations

Gnomad AFR

AF:

0.000927

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00166

Gnomad ASJ

AF:

0.00338

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000352

Gnomad FIN

AF:

0.00346

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00718

Gnomad OTH

AF:

0.00389

GnomAD3 exomes

AF:

0.00405

AC:

714

AN:

176082

Hom.:

AF XY:

0.00442

AC XY:

287

AN XY:

64914

show subpopulations

Gnomad AFR exome

AF:

0.00102

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00356

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000267

Gnomad FIN exome

AF:

0.00425

Gnomad NFE exome

AF:

0.00716

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00666

AC:

7295

AN:

1095468

Hom.:

Cov.:

AF XY:

0.00637

AC XY:

2308

AN XY:

362162

show subpopulations

Gnomad4 AFR exome

AF:

0.000987

Gnomad4 AMR exome

AF:

0.00125

Gnomad4 ASJ exome

AF:

0.00315

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000537

Gnomad4 FIN exome

AF:

0.00414

Gnomad4 NFE exome

AF:

0.00788

Gnomad4 OTH exome

AF:

0.00716

GnomAD4 genome

AF:

0.00413

AC:

469

AN:

113432

Hom.:

Cov.:

AF XY:

0.00343

AC XY:

122

AN XY:

35598

show subpopulations

Gnomad4 AFR

AF:

0.000925

Gnomad4 AMR

AF:

0.00166

Gnomad4 ASJ

AF:

0.00338

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000353

Gnomad4 FIN

AF:

0.00346

Gnomad4 NFE

AF:

0.00720

Gnomad4 OTH

AF:

0.00384

Alfa

AF:

0.00408

Hom.:

Bravo

AF:

0.00379

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00762

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00690

AC:

ExAC

AF:

0.00410

AC:

497

EpiCase

AF:

0.00556

EpiControl

AF:

0.00696

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 03, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.77

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.16

T;.;.;T

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.58

T;T;T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.0054

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;.;.;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.9

N;N;N;N

REVEL

Benign

0.20

Sift

Benign

0.031

D;D;D;D

Sift4G

Uncertain

0.037

D;T;T;T

Polyphen

0.96

D;P;D;.

Vest4

0.067

MVP

0.45

MPC

0.51

ClinPred

0.0060

GERP RS

2.2

Varity_R

0.030

gMVP

0.13

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