Genetic Variant IRAK1:p.Ser691Phe (chrX-154012537-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -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. 13/17 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

Publications

0 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=0.08743301).

BS2

High Hemizygotes in GnomAd4 at 6 Unknown gene

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	UniProt
IRAK1	NM_001569.4	MANE Select	c.2072C>T	p.Ser691Phe	missense	Exon 13 of 14	NP_001560.2	P51617-1
IRAK1	NM_001410701.1		c.2060C>T	p.Ser687Phe	missense	Exon 12 of 13	NP_001397630.1	D3YTB5
IRAK1	NM_001025242.2		c.1982C>T	p.Ser661Phe	missense	Exon 13 of 14	NP_001020413.1	P51617-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IRAK1	ENST00000369980.8	TSL:1 MANE Select	c.2072C>T	p.Ser691Phe	missense	Exon 13 of 14	ENSP00000358997.3	P51617-1
IRAK1	ENST00000393687.6	TSL:1	c.1982C>T	p.Ser661Phe	missense	Exon 13 of 14	ENSP00000377291.2	P51617-2
IRAK1	ENST00000369974.6	TSL:1	c.1835C>T	p.Ser612Phe	missense	Exon 12 of 13	ENSP00000358991.2	P51617-4

Frequencies

GnomAD3 genomes

AF:

0.000186

AC:

AN:

113116

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000622

AC:

AN:

176866

AF XY:

0.0000320

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 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

African (AFR)

AF:

0.000797

AC:

AN:

26348

American (AMR)

AF:

0.0000571

AC:

AN:

35012

Ashkenazi Jewish (ASJ)

AF:

0.0000521

AC:

AN:

19191

East Asian (EAS)

AF:

0.00

AC:

AN:

30150

South Asian (SAS)

AF:

0.00

AC:

AN:

53784

European-Finnish (FIN)

AF:

0.0000500

AC:

AN:

39985

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3995

European-Non Finnish (NFE)

AF:

0.0000107

AC:

AN:

840729

Other (OTH)

AF:

0.000131

AC:

AN:

45963

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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

AF:

0.000186

AC:

AN:

113116

Hom.:

Cov.:

AF XY:

0.000170

AC XY:

AN XY:

35250

show subpopulations

African (AFR)

AF:

0.000577

AC:

AN:

31193

American (AMR)

AF:

0.00

AC:

AN:

10790

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2660

East Asian (EAS)

AF:

0.00

AC:

AN:

3597

South Asian (SAS)

AF:

0.00

AC:

AN:

2796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6303

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000375

AC:

AN:

53323

Other (OTH)

AF:

0.000654

AC:

AN:

1529

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.000204

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

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

PhyloP100

3.0

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

Varity_R

0.10

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Computational scores

Splicing

Publications

Other links and lift over