rs1059703

chrX-154013378-G-AchrX-154013378-G-C

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.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. 14/19 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 0.73 (22192 hom., 24385 hem., cov: 24)
  • Exomes 𝑓: 0.80 (246066 hom. 281652 hem.)
  • Failed GnomAD Quality Control
• Consequence: IRAK1 NM_001569.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.346

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=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 id is 2688071.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 22197 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRAK1	NM_001569.4	c.1595C>T	p.Ser532Leu	missense_variant	12/14	ENST00000369980.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRAK1	ENST00000369980.8	c.1595C>T	p.Ser532Leu	missense_variant	12/14	1	NM_001569.4	P1

Frequencies

GnomAD3 genomes AF: 0.732 AC: 81784 AN: 111738 Hom.: 22197 Cov.: 24 AF XY: 0.717 AC XY: 24354 AN XY: 33944

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

GnomAD3 exomes AF: 0.674 AC: 110671 AN: 164305 Hom.: 26813 AF XY: 0.681 AC XY: 38591 AN XY: 56707

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 SAS exome AF: 0.406

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.: 41 AF XY: 0.788 AC XY: 281652 AN XY: 357396

Gnomad4 AFR exome AF: 0.653

Gnomad4 AMR exome AF: 0.469

Gnomad4 ASJ exome AF: 0.750

Gnomad4 EAS exome AF: 0.235

Gnomad4 SAS exome AF: 0.418

Gnomad4 FIN exome AF: 0.844

Gnomad4 NFE exome AF: 0.865

Gnomad4 OTH exome AF: 0.744

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.732 AC: 81802 AN: 111794 Hom.: 22192 Cov.: 24 AF XY: 0.717 AC XY: 24385 AN XY: 34010

Gnomad4 AFR AF: 0.648

Gnomad4 AMR AF: 0.568

Gnomad4 ASJ AF: 0.777

Gnomad4 EAS AF: 0.225

Gnomad4 SAS AF: 0.376

Gnomad4 FIN AF: 0.839

Gnomad4 NFE AF: 0.849

Gnomad4 OTH AF: 0.693

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

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 61% of patients studied by a panel of primary immunodeficiencies. Number of patients: 58. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	2.0
Dann	Benign	0.81
DEOGEN2	Benign	0.043	T;.
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.47	T;T
MetaRNN	Benign	0.0000034	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.55	N;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.62	N;N
REVEL	Benign	0.12
Sift	Benign	0.30	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.0	B;B
Vest4		0.012
MPC		0.42
ClinPred		0.0052	T
GERP RS		-0.87
Varity_R		0.037
gMVP		0.20

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: rs1059703; hg19: chrX-153278829; COSMIC: COSV64110800; COSMIC: COSV64110800;