X-154014121-G-C

Variant summary

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

The NM_001569.4(IRAK1):c.1460C>G(p.Pro487Arg) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P487A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: IRAK1 NM_001569.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.938

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRAK1	NM_001569.4	c.1460C>G	p.Pro487Arg	missense_variant	11/14	ENST00000369980.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRAK1	ENST00000369980.8	c.1460C>G	p.Pro487Arg	missense_variant	11/14	1	NM_001569.4	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

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

Dec 06, 2021

The c.1460C>G (p.P487R) alteration is located in exon 11 (coding exon 11) of the IRAK1 gene. This alteration results from a C to G substitution at nucleotide position 1460, causing the proline (P) at amino acid position 487 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	0.088
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.084	T;T;.;T
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.73	N;.;N;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.2	N;D;N;N
REVEL	Benign	0.067
Sift	Uncertain	0.022	D;D;T;T
Sift4G	Benign	0.36	T;D;T;T
Polyphen		1.0	D;.;D;.
Vest4		0.18
MutPred		0.49		Loss of glycosylation at P487 (P = 0.0786);.;Loss of glycosylation at P487 (P = 0.0786);.;
MVP		0.61
MPC		1.4
ClinPred		0.55	D
GERP RS		1.1
Varity_R		0.17
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		Position offset: 1

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-153279572;