X-154013378-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001569.4(IRAK1):c.1595C>T(p.Ser532Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.73 ( 22192 hom., 24385 hem., cov: 24)

Exomes 𝑓: 0.80 ( 246066 hom. 281652 hem. )

Failed GnomAD Quality Control

Consequence

IRAK1
NM_001569.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.346

Publications

95 publications found

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 Gene-Disease associations (from GenCC):

systemic lupus erythematosus
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

IRAK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.4482873E-6).

BP6

Variant X-154013378-G-A is Benign according to our data. Variant chrX-154013378-G-A is described in ClinVar as Benign. ClinVar VariationId is 2688071.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001569.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IRAK1	NM_001569.4	MANE Select	c.1595C>T	p.Ser532Leu	missense	Exon 12 of 14	NP_001560.2
IRAK1	NM_001025243.2		c.1358C>T	p.Ser453Leu	missense	Exon 11 of 13	NP_001020414.1
IRAK1	NM_001410701.1		c.1618-35C>T		intron	N/A	NP_001397630.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IRAK1	ENST00000369980.8	TSL:1 MANE Select	c.1595C>T	p.Ser532Leu	missense	Exon 12 of 14	ENSP00000358997.3
IRAK1	ENST00000369974.6	TSL:1	c.1358C>T	p.Ser453Leu	missense	Exon 11 of 13	ENSP00000358991.2
IRAK1	ENST00000393687.6	TSL:1	c.1540-35C>T		intron	N/A	ENSP00000377291.2

Frequencies

GnomAD3 genomes

AF:

0.732

AC:

81784

AN:

111738

Hom.:

22197

Cov.:

show subpopulations

Gnomad AFR

AF:

0.649

Gnomad AMI

AF:

0.961

Gnomad AMR

AF:

0.569

Gnomad ASJ

AF:

0.777

Gnomad EAS

AF:

0.226

Gnomad SAS

AF:

0.374

Gnomad FIN

AF:

0.839

Gnomad MID

AF:

0.693

Gnomad NFE

AF:

0.849

Gnomad OTH

AF:

0.693

GnomAD2 exomes

AF:

0.674

AC:

110671

AN:

164305

AF XY:

0.681

show subpopulations

Gnomad AFR exome

AF:

0.636

Gnomad AMR exome

AF:

0.459

Gnomad ASJ exome

AF:

0.753

Gnomad EAS exome

AF:

0.217

Gnomad FIN exome

AF:

0.841

Gnomad NFE exome

AF:

0.850

Gnomad OTH exome

AF:

0.707

GnomAD4 exome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.800

AC:

870719

AN:

1088268

Hom.:

246066

Cov.:

AF XY:

0.788

AC XY:

281652

AN XY:

357396

show subpopulations

African (AFR)

AF:

0.653

AC:

16866

AN:

25822

American (AMR)

AF:

0.469

AC:

15424

AN:

32853

Ashkenazi Jewish (ASJ)

AF:

0.750

AC:

14226

AN:

18980

East Asian (EAS)

AF:

0.235

AC:

7076

AN:

30085

South Asian (SAS)

AF:

0.418

AC:

22244

AN:

53186

European-Finnish (FIN)

AF:

0.844

AC:

33059

AN:

39183

Middle Eastern (MID)

AF:

0.607

AC:

2457

AN:

4051

European-Non Finnish (NFE)

AF:

0.865

AC:

725407

AN:

838441

Other (OTH)

AF:

0.744

AC:

33960

AN:

45667

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

5706

11412

17119

22825

28531

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19646

39292

58938

78584

98230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.732

AC:

81802

AN:

111794

Hom.:

22192

Cov.:

AF XY:

0.717

AC XY:

24385

AN XY:

34010

show subpopulations

African (AFR)

AF:

0.648

AC:

19973

AN:

30808

American (AMR)

AF:

0.568

AC:

6076

AN:

10702

Ashkenazi Jewish (ASJ)

AF:

0.777

AC:

2048

AN:

2636

East Asian (EAS)

AF:

0.225

AC:

791

AN:

3514

South Asian (SAS)

AF:

0.376

AC:

1029

AN:

2738

European-Finnish (FIN)

AF:

0.839

AC:

5110

AN:

6089

Middle Eastern (MID)

AF:

0.687

AC:

149

AN:

217

European-Non Finnish (NFE)

AF:

0.849

AC:

44916

AN:

52884

Other (OTH)

AF:

0.693

AC:

1061

AN:

1531

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

705

1410

2116

2821

3526

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

688

1376

2064

2752

3440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.794

Hom.:

12218

Bravo

AF:

0.707

TwinsUK

AF:

0.868

AC:

3220

ALSPAC

AF:

0.869

AC:

2510

ESP6500AA

AF:

0.652

AC:

2477

ESP6500EA

AF:

0.853

AC:

5660

ExAC

AF:

0.681

AC:

82019

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 61% of patients studied by a panel of primary immunodeficiencies. Number of patients: 58. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

2.0

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.043

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0000035

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.55

PhyloP100

-0.35

PrimateAI

Benign

0.29

PROVEAN

Benign

0.62

REVEL

Benign

0.12

Sift

Benign

0.30

Sift4G

Benign

0.31

Polyphen

0.0

Vest4

0.012

MPC

0.42

ClinPred

0.0052

GERP RS

-0.87

BranchPoint Hunter

1.0

Varity_R

0.037

gMVP

0.20

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over