X-154013150-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001569.4(IRAK1):c.1823G>T(p.Cys608Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 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)
• Consequence: IRAK1 NM_001569.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.280

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22079235).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRAK1	NM_001569.4	c.1823G>T	p.Cys608Phe	missense_variant	12/14	ENST00000369980.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRAK1	ENST00000369980.8	c.1823G>T	p.Cys608Phe	missense_variant	12/14	1	NM_001569.4	P1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 26

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

Jun 06, 2023

The c.1823G>T (p.C608F) alteration is located in exon 12 (coding exon 12) of the IRAK1 gene. This alteration results from a G to T substitution at nucleotide position 1823, causing the cysteine (C) at amino acid position 608 to be replaced by a phenylalanine (F). 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	0.077
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	8.2
Dann	Benign	0.95
DEOGEN2	Benign	0.34	T;.;.;T
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.1	M;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.9	D;D;D;D
REVEL	Benign	0.13
Sift	Uncertain	0.0070	D;D;D;D
Sift4G	Uncertain	0.036	D;D;T;D
Polyphen		0.79	P;B;P;.
Vest4		0.18
MutPred		0.10		Loss of glycosylation at S607 (P = 0.1389);.;.;.;
MVP		0.65
MPC		1.0
ClinPred		0.29	T
GERP RS		0.88
Varity_R		0.24
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-153278601;