X-154013099-G-A

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.1874C>T(p.Thr625Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00642 in 1,208,900 control chromosomes in the GnomAD database, including 22 homozygotes. There are 2,430 hemizygotes in GnomAD. 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0041 (2 hom., 122 hem., cov: 26)
  • Exomes 𝑓: 0.0067 (20 hom. 2308 hem.)
• Consequence: IRAK1 NM_001569.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.425

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=0.0053812265).
• BP6: Variant X-154013099-G-A is Benign according to our data. Variant chrX-154013099-G-A is described in ClinVar as [Benign]. Clinvar id is 787610.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154013099-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRAK1	NM_001569.4	c.1874C>T	p.Thr625Met	missense_variant	12/14	ENST00000369980.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRAK1	ENST00000369980.8	c.1874C>T	p.Thr625Met	missense_variant	12/14	1	NM_001569.4	P1

Frequencies

GnomAD3 genomes AF: 0.00413 AC: 468 AN: 113379 Hom.: 2 Cov.: 26 AF XY: 0.00343 AC XY: 122 AN XY: 35535

Gnomad AFR AF: 0.000927

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00166

Gnomad ASJ AF: 0.00338

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000352

Gnomad FIN AF: 0.00346

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00718

Gnomad OTH AF: 0.00389

GnomAD3 exomes AF: 0.00405 AC: 714 AN: 176082 Hom.: 0 AF XY: 0.00442 AC XY: 287 AN XY: 64914

Gnomad AFR exome AF: 0.00102

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00356

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000267

Gnomad FIN exome AF: 0.00425

Gnomad NFE exome AF: 0.00716

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00666 AC: 7295 AN: 1095468 Hom.: 20 Cov.: 32 AF XY: 0.00637 AC XY: 2308 AN XY: 362162

Gnomad4 AFR exome AF: 0.000987

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.00315

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000537

Gnomad4 FIN exome AF: 0.00414

Gnomad4 NFE exome AF: 0.00788

Gnomad4 OTH exome AF: 0.00716

GnomAD4 genome AF: 0.00413 AC: 469 AN: 113432 Hom.: 2 Cov.: 26 AF XY: 0.00343 AC XY: 122 AN XY: 35598

Gnomad4 AFR AF: 0.000925

Gnomad4 AMR AF: 0.00166

Gnomad4 ASJ AF: 0.00338

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000353

Gnomad4 FIN AF: 0.00346

Gnomad4 NFE AF: 0.00720

Gnomad4 OTH AF: 0.00384

Alfa AF: 0.00408 Hom.: 30

Bravo AF: 0.00379

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00762 AC: 22

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00690 AC: 46

ExAC AF: 0.00410 AC: 497

EpiCase AF: 0.00556

EpiControl AF: 0.00696

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Sep 03, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	13
Dann	Benign	0.97
DEOGEN2	Benign	0.16	T;.;.;T
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.58	T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0054	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.031	D;D;D;D
Sift4G	Uncertain	0.037	D;T;T;T
Polyphen		0.96	D;P;D;.
Vest4		0.067
MVP		0.45
MPC		0.51
ClinPred		0.0060	T
GERP RS		2.2
Varity_R		0.030
gMVP		0.13

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: rs35638718; hg19: chrX-153278550;