X-154013175-G-T

Variant names:

• chrX-154013175-G-T
• rs199501854
• NM_001569.4:c.1798C>A

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.1798C>A​(p.Arg600Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,094,847 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 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. R600C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: IRAK1 NM_001569.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0870
• 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=0.07030621).

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.1798C>A	p.Arg600Ser	missense	Exon 12 of 14	NP_001560.2	P51617-1
	IRAK1	NM_001410701.1		c.1786C>A	p.Arg596Ser	missense	Exon 11 of 13	NP_001397630.1	D3YTB5
	IRAK1	NM_001025242.2		c.1708C>A	p.Arg570Ser	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.1798C>A	p.Arg600Ser	missense	Exon 12 of 14	ENSP00000358997.3	P51617-1
	IRAK1	ENST00000393687.6	TSL:1	c.1708C>A	p.Arg570Ser	missense	Exon 12 of 14	ENSP00000377291.2	P51617-2
	IRAK1	ENST00000369974.6	TSL:1	c.1561C>A	p.Arg521Ser	missense	Exon 11 of 13	ENSP00000358991.2	P51617-4

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD2 exomes AF: 0.00 AC: 0 AN: 172543 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1094847 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 361445

African (AFR) AF: 0.00 AC: 0 AN: 26325

American (AMR) AF: 0.00 AC: 0 AN: 35092

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19337

East Asian (EAS) AF: 0.00 AC: 0 AN: 30087

South Asian (SAS) AF: 0.00 AC: 0 AN: 53854

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3429

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841471

Other (OTH) AF: 0.00 AC: 0 AN: 45934

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Benign	0.94
DEOGEN2	Benign	0.076	T
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.38	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.087
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.11
Sift	Benign	0.53	T
Sift4G	Benign	0.43	T
Polyphen		0.0020	B
Vest4		0.059
MutPred		0.19		Gain of phosphorylation at R600 (P = 0.0551)
MVP		0.60
MPC		0.54
ClinPred		0.053	T
GERP RS		-0.063
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.15
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs199501854; hg19: chrX-153278626;