X-154012537-G-C

Variant names:

• chrX-154012537-G-C
• rs147444875
• NM_001569.4:c.2072C>G

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.2072C>G​(p.Ser691Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,095,157 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/17 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. S691F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 hem.)
• Consequence: IRAK1 NM_001569.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.97
• 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=0.23927543).
• BS2: High Hemizygotes in GnomAdExome4 at 2 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.2072C>G	p.Ser691Cys	missense	Exon 13 of 14	NP_001560.2	P51617-1
	IRAK1	NM_001410701.1		c.2060C>G	p.Ser687Cys	missense	Exon 12 of 13	NP_001397630.1	D3YTB5
	IRAK1	NM_001025242.2		c.1982C>G	p.Ser661Cys	missense	Exon 13 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.2072C>G	p.Ser691Cys	missense	Exon 13 of 14	ENSP00000358997.3	P51617-1
	IRAK1	ENST00000393687.6	TSL:1	c.1982C>G	p.Ser661Cys	missense	Exon 13 of 14	ENSP00000377291.2	P51617-2
	IRAK1	ENST00000369974.6	TSL:1	c.1835C>G	p.Ser612Cys	missense	Exon 12 of 13	ENSP00000358991.2	P51617-4

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000548 AC: 6 AN: 1095157 Hom.: 0 Cov.: 31 AF XY: 0.00000554 AC XY: 2 AN XY: 361141

African (AFR) AF: 0.00 AC: 0 AN: 26348

American (AMR) AF: 0.00 AC: 0 AN: 35012

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19191

East Asian (EAS) AF: 0.00 AC: 0 AN: 30150

South Asian (SAS) AF: 0.00 AC: 0 AN: 53784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39985

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3995

European-Non Finnish (NFE) AF: 0.00000714 AC: 6 AN: 840729

Other (OTH) AF: 0.00 AC: 0 AN: 45963

GnomAD4 genome Cov.: 25

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.019	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.0
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.030
Sift	Benign	0.31	T
Sift4G	Benign	0.43	T
MVP		0.56
ClinPred		0.88	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
Mutation Taster		=97/3	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: rs147444875; hg19: chrX-153277988;