rs1059702

Variant names:

• chrX-154018741-A-G
• rs1059702
• NM_001569.4:c.587T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001569.4(IRAK1):​c.587T>C​(p.Phe196Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (★).

• Frequency:
  • Genomes: 𝑓 0.83 (28339 hom., 24998 hem., cov: 21)
  • Exomes 𝑓: 0.81 (227179 hom. 218495 hem.)
  • Failed GnomAD Quality Control
• Consequence: IRAK1 NM_001569.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.94
• Publications: 114 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=1.6834772E-6).
• BP6: Variant X-154018741-A-G is Benign according to our data. Variant chrX-154018741-A-G is described in ClinVar as Benign. ClinVar VariationId is 2688060.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK1	NM_001569.4	MANE Select	c.587T>C	p.Phe196Ser	missense	Exon 5 of 14	NP_001560.2	P51617-1
	IRAK1	NM_001410701.1		c.665T>C	p.Phe222Ser	missense	Exon 4 of 13	NP_001397630.1	D3YTB5
	IRAK1	NM_001025242.2		c.587T>C	p.Phe196Ser	missense	Exon 5 of 14	NP_001020413.1	P51617-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK1	ENST00000369980.8	TSL:1 MANE Select	c.587T>C	p.Phe196Ser	missense	Exon 5 of 14	ENSP00000358997.3	P51617-1
	IRAK1	ENST00000393687.6	TSL:1	c.587T>C	p.Phe196Ser	missense	Exon 5 of 14	ENSP00000377291.2	P51617-2
	IRAK1	ENST00000369974.6	TSL:1	c.587T>C	p.Phe196Ser	missense	Exon 5 of 13	ENSP00000358991.2	P51617-4

Frequencies

GnomAD3 genomes AF: 0.829 AC: 90140 AN: 108668 Hom.: 28337 Cov.: 21

Gnomad AFR AF: 0.956

Gnomad AMI AF: 0.962

Gnomad AMR AF: 0.620

Gnomad ASJ AF: 0.779

Gnomad EAS AF: 0.233

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.844

Gnomad MID AF: 0.708

Gnomad NFE AF: 0.860

Gnomad OTH AF: 0.768

GnomAD2 exomes AF: 0.716 AC: 129023 AN: 180099 AF XY: 0.714

Gnomad AFR exome AF: 0.957

Gnomad AMR exome AF: 0.510

Gnomad ASJ exome AF: 0.758

Gnomad EAS exome AF: 0.226

Gnomad FIN exome AF: 0.845

Gnomad NFE exome AF: 0.864

Gnomad OTH exome AF: 0.734

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.814 AC: 753155 AN: 924891 Hom.: 227179 Cov.: 20 AF XY: 0.799 AC XY: 218495 AN XY: 273467

African (AFR) AF: 0.963 AC: 22415 AN: 23268

American (AMR) AF: 0.519 AC: 18058 AN: 34794

Ashkenazi Jewish (ASJ) AF: 0.757 AC: 13830 AN: 18281

East Asian (EAS) AF: 0.240 AC: 7036 AN: 29340

South Asian (SAS) AF: 0.457 AC: 22969 AN: 50310

European-Finnish (FIN) AF: 0.848 AC: 34139 AN: 40244

Middle Eastern (MID) AF: 0.637 AC: 2393 AN: 3758

European-Non Finnish (NFE) AF: 0.878 AC: 601112 AN: 684694

Other (OTH) AF: 0.776 AC: 31203 AN: 40202

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.830 AC: 90196 AN: 108722 Hom.: 28339 Cov.: 21 AF XY: 0.806 AC XY: 24998 AN XY: 30998

African (AFR) AF: 0.957 AC: 28387 AN: 29676

American (AMR) AF: 0.619 AC: 6417 AN: 10371

Ashkenazi Jewish (ASJ) AF: 0.779 AC: 2035 AN: 2611

East Asian (EAS) AF: 0.233 AC: 797 AN: 3423

South Asian (SAS) AF: 0.413 AC: 1020 AN: 2470

European-Finnish (FIN) AF: 0.844 AC: 4781 AN: 5666

Middle Eastern (MID) AF: 0.698 AC: 150 AN: 215

European-Non Finnish (NFE) AF: 0.860 AC: 44837 AN: 52150

Other (OTH) AF: 0.767 AC: 1131 AN: 1474

Alfa AF: 0.828 Hom.: 138015

Bravo AF: 0.817

TwinsUK AF: 0.875 AC: 3243

ALSPAC AF: 0.877 AC: 2534

ESP6500AA AF: 0.955 AC: 3663

ESP6500EA AF: 0.860 AC: 5783

ExAC AF: 0.727 AC: 88198

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.81
DEOGEN2	Benign	0.041	T
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.091	T
MetaRNN	Benign	0.0000017	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.3	N
PhyloP100		2.9
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.044
Sift	Benign	0.80	T
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.024
MPC		0.85
ClinPred		0.00083	T
GERP RS		3.7
PromoterAI		-0.055	Neutral
Varity_R		0.36
gMVP		0.47
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1059702; hg19: chrX-153284192; COSMIC: COSV57652216; COSMIC: COSV57652216;