NM_001569.4:c.1472T>C

Variant names:

• chrX-154014109-A-G
• rs782357859
• NM_001569.4:c.1472T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001569.4(IRAK1):​c.1472T>C​(p.Leu491Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000343 in 1,194,321 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000028 (0 hom. 12 hem.)
• Consequence: IRAK1 NM_001569.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.733
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18452263).
• BS2: High Hemizygotes in GnomAdExome4 at 12 Unknown gene

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.1472T>C	p.Leu491Pro	missense	Exon 11 of 14	NP_001560.2	P51617-1
	IRAK1	NM_001410701.1		c.1550T>C	p.Leu517Pro	missense	Exon 10 of 13	NP_001397630.1	D3YTB5
	IRAK1	NM_001025242.2		c.1472T>C	p.Leu491Pro	missense	Exon 11 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.1472T>C	p.Leu491Pro	missense	Exon 11 of 14	ENSP00000358997.3	P51617-1
	IRAK1	ENST00000393687.6	TSL:1	c.1472T>C	p.Leu491Pro	missense	Exon 11 of 14	ENSP00000377291.2	P51617-2
	IRAK1	ENST00000369974.6	TSL:1	c.1303-676T>C		intron	N/A	ENSP00000358991.2	P51617-4

Frequencies

GnomAD3 genomes AF: 0.0000991 AC: 11 AN: 110960 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000655

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000188

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000751

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000949

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000246 AC: 4 AN: 162544 AF XY: 0.0000530

Gnomad AFR exome AF: 0.000265

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: 0.0000137

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000277 AC: 30 AN: 1083316 Hom.: 0 Cov.: 32 AF XY: 0.0000339 AC XY: 12 AN XY: 353936

African (AFR) AF: 0.000118 AC: 3 AN: 25493

American (AMR) AF: 0.00 AC: 0 AN: 31580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18937

East Asian (EAS) AF: 0.0000664 AC: 2 AN: 30108

South Asian (SAS) AF: 0.00 AC: 0 AN: 52196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39597

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3576

European-Non Finnish (NFE) AF: 0.0000299 AC: 25 AN: 836386

Other (OTH) AF: 0.00 AC: 0 AN: 45443

GnomAD4 genome AF: 0.0000991 AC: 11 AN: 111005 Hom.: 0 Cov.: 22 AF XY: 0.0000301 AC XY: 1 AN XY: 33261

African (AFR) AF: 0.0000653 AC: 2 AN: 30605

American (AMR) AF: 0.000188 AC: 2 AN: 10627

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2630

East Asian (EAS) AF: 0.00 AC: 0 AN: 3472

South Asian (SAS) AF: 0.000754 AC: 2 AN: 2652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5951

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.0000950 AC: 5 AN: 52654

Other (OTH) AF: 0.00 AC: 0 AN: 1525

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000498 AC: 6

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	0.24
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.73
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.17
Sift	Benign	0.089	T
Sift4G	Benign	0.30	T
Polyphen		0.97	D
Vest4		0.69
MutPred		0.48		Loss of catalytic residue at L491 (P = 0.012)
MVP		0.76
MPC		1.7
ClinPred		0.85	D
GERP RS		1.5
PromoterAI		-0.043	Neutral
Varity_R		0.77
gMVP		0.89
Mutation Taster		=100/0	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: rs782357859; hg19: chrX-153279560; COSMIC: COSV105919148;