X-154013378-G-C

Variant names:

• chrX-154013378-G-C
• rs1059703
• NM_001569.4:c.1595C>G

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.1595C>G​(p.Ser532Trp) 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. 16/21 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. S532L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: IRAK1 NM_001569.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.346
• Publications: 95 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=0.14391571).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK1	NM_001569.4	MANE Select	c.1595C>G	p.Ser532Trp	missense	Exon 12 of 14	NP_001560.2
	IRAK1	NM_001025243.2		c.1358C>G	p.Ser453Trp	missense	Exon 11 of 13	NP_001020414.1
	IRAK1	NM_001410701.1		c.1618-35C>G		intron	N/A	NP_001397630.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK1	ENST00000369980.8	TSL:1 MANE Select	c.1595C>G	p.Ser532Trp	missense	Exon 12 of 14	ENSP00000358997.3
	IRAK1	ENST00000369974.6	TSL:1	c.1358C>G	p.Ser453Trp	missense	Exon 11 of 13	ENSP00000358991.2
	IRAK1	ENST00000393687.6	TSL:1	c.1540-35C>G		intron	N/A	ENSP00000377291.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.35
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.27
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.017	D
Polyphen		0.94	P
Vest4		0.20
MutPred		0.29		Loss of disorder (P = 4e-04)
MVP		0.68
MPC		1.2
ClinPred		0.25	T
GERP RS		-0.87
BranchPoint Hunter		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.042
gMVP		0.34
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1059703; hg19: chrX-153278829;