chrX-154013069-G-A

Variant names:

• chrX-154013069-G-A
• rs1557127956
• NM_001569.4:c.1904C>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.1904C>T​(p.Pro635Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P635R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 26)
• Consequence: IRAK1 NM_001569.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.264
• 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=0.102071345).

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.1904C>T	p.Pro635Leu	missense	Exon 12 of 14	NP_001560.2	P51617-1
	IRAK1	NM_001410701.1		c.1892C>T	p.Pro631Leu	missense	Exon 11 of 13	NP_001397630.1	D3YTB5
	IRAK1	NM_001025242.2		c.1814C>T	p.Pro605Leu	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.1904C>T	p.Pro635Leu	missense	Exon 12 of 14	ENSP00000358997.3	P51617-1
	IRAK1	ENST00000393687.6	TSL:1	c.1814C>T	p.Pro605Leu	missense	Exon 12 of 14	ENSP00000377291.2	P51617-2
	IRAK1	ENST00000369974.6	TSL:1	c.1667C>T	p.Pro556Leu	missense	Exon 11 of 13	ENSP00000358991.2	P51617-4

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.0
DANN	Benign	0.97
DEOGEN2	Benign	0.18	T
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-0.26
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.015
Sift	Benign	0.27	T
Sift4G	Uncertain	0.059	T
Polyphen		0.70	P
Vest4		0.060
MutPred		0.13		Loss of glycosylation at P635 (P = 0.0224)
MVP		0.58
MPC		0.49
ClinPred		0.23	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.049
gMVP		0.27
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1557127956; hg19: chrX-153278520;