chrX-154013385-C-T

Variant names:

• chrX-154013385-C-T
• rs368063747
• NM_001569.4:c.1588G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001569.4(IRAK1):​c.1588G>A​(p.Gly530Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000328 in 1,198,201 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 129 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 5 hem., cov: 25)
  • Exomes 𝑓: 0.00035 (0 hom. 124 hem.)
• Consequence: IRAK1 NM_001569.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.328
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.045195907).
• BS2: High Hemizygotes in GnomAd4 at 5 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.1588G>A	p.Gly530Arg	missense	Exon 12 of 14	NP_001560.2	P51617-1
	IRAK1	NM_001025243.2		c.1351G>A	p.Gly451Arg	missense	Exon 11 of 13	NP_001020414.1	P51617-4
	IRAK1	NM_001410701.1		c.1618-42G>A		intron	N/A	NP_001397630.1	D3YTB5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK1	ENST00000369980.8	TSL:1 MANE Select	c.1588G>A	p.Gly530Arg	missense	Exon 12 of 14	ENSP00000358997.3	P51617-1
	IRAK1	ENST00000369974.6	TSL:1	c.1351G>A	p.Gly451Arg	missense	Exon 11 of 13	ENSP00000358991.2	P51617-4
	IRAK1	ENST00000393687.6	TSL:1	c.1540-42G>A		intron	N/A	ENSP00000377291.2	P51617-2

Frequencies

GnomAD3 genomes AF: 0.000124 AC: 14 AN: 112881 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000263

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000924 AC: 15 AN: 162307 AF XY: 0.000125

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000415

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000349 AC: 379 AN: 1085320 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 124 AN XY: 354940

African (AFR) AF: 0.000117 AC: 3 AN: 25670

American (AMR) AF: 0.0000310 AC: 1 AN: 32289

Ashkenazi Jewish (ASJ) AF: 0.0000532 AC: 1 AN: 18789

East Asian (EAS) AF: 0.00 AC: 0 AN: 30094

South Asian (SAS) AF: 0.00 AC: 0 AN: 52662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4041

European-Non Finnish (NFE) AF: 0.000425 AC: 356 AN: 837349

Other (OTH) AF: 0.000395 AC: 18 AN: 45526

GnomAD4 genome AF: 0.000124 AC: 14 AN: 112881 Hom.: 0 Cov.: 25 AF XY: 0.000143 AC XY: 5 AN XY: 35025

African (AFR) AF: 0.00 AC: 0 AN: 31098

American (AMR) AF: 0.00 AC: 0 AN: 10784

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3583

South Asian (SAS) AF: 0.00 AC: 0 AN: 2778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.000263 AC: 14 AN: 53211

Other (OTH) AF: 0.00 AC: 0 AN: 1529

Alfa AF: 0.000304 Hom.: 3

Bravo AF: 0.000117

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000605 AC: 4

ExAC AF: 0.0000994 AC: 12

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	0.084
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.30
DANN	Benign	0.48
DEOGEN2	Benign	0.096	T
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.33
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.12
Sift	Benign	0.35	T
Sift4G	Benign	0.68	T
Polyphen		0.0020	B
Vest4		0.082
MutPred		0.17		Gain of MoRF binding (P = 0.0504)
MVP		0.51
MPC		0.57
ClinPred		0.039	T
GERP RS		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.093
gMVP		0.30
Mutation Taster		=96/4	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: rs368063747; hg19: chrX-153278836;