chrX-154013150-C-A

Variant names:

• chrX-154013150-C-A
• rs1557127993
• NM_001569.4:c.1823G>T

Variant summary

Our verdict is Uncertain significance. The variant received 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. 13/21 in silico tools predict 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. C608Y) has been classified 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
• Publications: 0 publications found

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]

IRAK1 Gene-Disease associations (from GenCC):

• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001569.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK1	NM_001569.4	MANE Select	c.1823G>T	p.Cys608Phe	missense	Exon 12 of 14	NP_001560.2	P51617-1
	IRAK1	NM_001410701.1		c.1811G>T	p.Cys604Phe	missense	Exon 11 of 13	NP_001397630.1	D3YTB5
	IRAK1	NM_001025242.2		c.1733G>T	p.Cys578Phe	missense	Exon 12 of 14	NP_001020413.1	P51617-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK1	ENST00000369980.8	TSL:1 MANE Select	c.1823G>T	p.Cys608Phe	missense	Exon 12 of 14	ENSP00000358997.3	P51617-1
	IRAK1	ENST00000393687.6	TSL:1	c.1733G>T	p.Cys578Phe	missense	Exon 12 of 14	ENSP00000377291.2	P51617-2
	IRAK1	ENST00000369974.6	TSL:1	c.1586G>T	p.Cys529Phe	missense	Exon 11 of 13	ENSP00000358991.2	P51617-4

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 26

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.28
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.13
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.036	D
Polyphen		0.79	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
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs1557127993; hg19: chrX-153278601;