rs1059702

chrX-154018741-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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]

ACMG classification

Verdict is Benign. Variant got -10 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 id is 2688060.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 28337 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRAK1	NM_001569.4	c.587T>C	p.Phe196Ser	missense_variant	5/14	ENST00000369980.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRAK1	ENST00000369980.8	c.587T>C	p.Phe196Ser	missense_variant	5/14	1	NM_001569.4	P1

Frequencies

GnomAD3 genomes AF: 0.829 AC: 90140 AN: 108668 Hom.: 28337 Cov.: 21 AF XY: 0.806 AC XY: 24939 AN XY: 30934

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

GnomAD3 exomes AF: 0.716 AC: 129023 AN: 180099 Hom.: 32457 AF XY: 0.714 AC XY: 46671 AN XY: 65321

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 SAS exome AF: 0.448

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

Gnomad4 AFR exome AF: 0.963

Gnomad4 AMR exome AF: 0.519

Gnomad4 ASJ exome AF: 0.757

Gnomad4 EAS exome AF: 0.240

Gnomad4 SAS exome AF: 0.457

Gnomad4 FIN exome AF: 0.848

Gnomad4 NFE exome AF: 0.878

Gnomad4 OTH exome AF: 0.776

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

Gnomad4 AFR AF: 0.957

Gnomad4 AMR AF: 0.619

Gnomad4 ASJ AF: 0.779

Gnomad4 EAS AF: 0.233

Gnomad4 SAS AF: 0.413

Gnomad4 FIN AF: 0.844

Gnomad4 NFE AF: 0.860

Gnomad4 OTH AF: 0.767

Alfa AF: 0.825 Hom.: 102481

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 62% of patients studied by a panel of primary immunodeficiencies. Number of patients: 59. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

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;.;.;T
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.091	T;T;T;T
MetaRNN	Benign	0.0000017	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.3	N;N;N;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.7	N;N;N;N
REVEL	Benign	0.044
Sift	Benign	0.80	T;T;T;T
Sift4G	Benign	0.54	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.024
MPC		0.85
ClinPred		0.00083	T
GERP RS		3.7
Varity_R		0.36
gMVP		0.47

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

LitVar

Other links and lift over

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