X-154013174-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001569.4(IRAK1):c.1799G>A(p.Arg600His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,208,587 control chromosomes in the GnomAD database, including 21 homozygotes. There are 724 hemizygotes in GnomAD. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R600C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., 39 hem., cov: 26)
  • Exomes 𝑓: 0.0012 (21 hom. 685 hem.)
• Consequence: IRAK1 NM_001569.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.648

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022255778).
• BP6: Variant X-154013174-C-T is Benign according to our data. Variant chrX-154013174-C-T is described in ClinVar as [Benign]. Clinvar id is 746901.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000564 (64/113568) while in subpopulation SAS AF= 0.02 (57/2857). AF 95% confidence interval is 0.0158. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 39 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRAK1	NM_001569.4	c.1799G>A	p.Arg600His	missense_variant	12/14	ENST00000369980.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRAK1	ENST00000369980.8	c.1799G>A	p.Arg600His	missense_variant	12/14	1	NM_001569.4	P1

Frequencies

GnomAD3 genomes AF: 0.000573 AC: 65 AN: 113515 Hom.: 0 Cov.: 26 AF XY: 0.00109 AC XY: 39 AN XY: 35643

Gnomad AFR AF: 0.000128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000553

Gnomad SAS AF: 0.0202

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000187

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00278 AC: 480 AN: 172863 Hom.: 8 AF XY: 0.00414 AC XY: 256 AN XY: 61849

Gnomad AFR exome AF: 0.000170

Gnomad AMR exome AF: 0.0000370

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000151

Gnomad SAS exome AF: 0.0252

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000397

Gnomad OTH exome AF: 0.00185

GnomAD4 exome AF: 0.00118 AC: 1291 AN: 1095019 Hom.: 21 Cov.: 32 AF XY: 0.00189 AC XY: 685 AN XY: 361575

Gnomad4 AFR exome AF: 0.0000380

Gnomad4 AMR exome AF: 0.0000285

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0210

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000463

Gnomad4 OTH exome AF: 0.00250

GnomAD4 genome AF: 0.000564 AC: 64 AN: 113568 Hom.: 0 Cov.: 26 AF XY: 0.00109 AC XY: 39 AN XY: 35706

Gnomad4 AFR AF: 0.000128

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000555

Gnomad4 SAS AF: 0.0200

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000187

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000608 Hom.: 6

Bravo AF: 0.000189

ExAC AF: 0.00325 AC: 394

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	0.015
Dann	Benign	0.81
DEOGEN2	Benign	0.043	T;.;.;T
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.37	T;T;T;T
MetaRNN	Benign	0.0022	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.0	N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.90	N;N;N;N
REVEL	Benign	0.065
Sift	Benign	0.68	T;T;T;T
Sift4G	Benign	0.46	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.018
MutPred		0.24		Loss of phosphorylation at S601 (P = 0.1581);.;.;.;
MVP		0.51
MPC		0.59
ClinPred		0.0035	T
GERP RS		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.021
gMVP		0.11

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

LitVar

Other links and lift over

dbSNP: rs782780153; hg19: chrX-153278625; COSMIC: COSV64111958; COSMIC: COSV64111958;