X-154013292-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001569.4(IRAK1):c.1681T>C(p.Trp561Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,095,126 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: IRAK1 NM_001569.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.30

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043940127).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRAK1	NM_001569.4	c.1681T>C	p.Trp561Arg	missense_variant	12/14	ENST00000369980.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRAK1	ENST00000369980.8	c.1681T>C	p.Trp561Arg	missense_variant	12/14	1	NM_001569.4	P1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD3 exomes AF: 0.0000175 AC: 3 AN: 171920 Hom.: 0 AF XY: 0.0000159 AC XY: 1 AN XY: 62950

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000225

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1095126 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 1 AN XY: 361428

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000663

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 26

ExAC AF: 0.0000331 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2024

The c.1681T>C (p.W561R) alteration is located in exon 12 (coding exon 12) of the IRAK1 gene. This alteration results from a T to C substitution at nucleotide position 1681, causing the tryptophan (W) at amino acid position 561 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.13
Dann	Benign	0.45
DEOGEN2	Benign	0.32	T;.;.;T
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.44	T;T;T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.044	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.89	L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.7	D;N;D;D
REVEL	Benign	0.014
Sift	Benign	0.22	T;T;T;T
Sift4G	Benign	0.36	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.041
MutPred		0.23		Gain of methylation at W561 (P = 0.067);.;.;.;
MVP		0.23
MPC		0.85
ClinPred		0.90	D
GERP RS		-7.6
Varity_R		0.14
gMVP		0.29

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: rs782687454; hg19: chrX-153278743;