chrX-154018721-A-T

Position:

• chrX-154018721-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000369980.8(IRAK1):​c.607T>A​(p.Cys203Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00351 in 1,087,651 control chromosomes in the GnomAD database, including 106 homozygotes. There are 925 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.017 (50 hom., 466 hem., cov: 22)
  • Exomes 𝑓: 0.0019 (56 hom. 459 hem.)
• Consequence: IRAK1 ENST00000369980.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.184

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017255843).
• BP6: Variant X-154018721-A-T is Benign according to our data. Variant chrX-154018721-A-T is described in ClinVar as [Benign]. Clinvar id is 781577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.057 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRAK1	NM_001569.4	c.607T>A	p.Cys203Ser	missense_variant	5/14	ENST00000369980.8	NP_001560.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRAK1	ENST00000369980.8	c.607T>A	p.Cys203Ser	missense_variant	5/14	1	NM_001569.4	ENSP00000358997	P1

Frequencies

GnomAD3 genomes AF: 0.0174 AC: 1915 AN: 109841 Hom.: 50 Cov.: 22 AF XY: 0.0144 AC XY: 464 AN XY: 32143

Gnomad AFR AF: 0.0593

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000399

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00844

Gnomad NFE AF: 0.000152

Gnomad OTH AF: 0.0130

GnomAD3 exomes AF: 0.00507 AC: 923 AN: 182162 Hom.: 21 AF XY: 0.00310 AC XY: 208 AN XY: 67010

Gnomad AFR exome AF: 0.0628

Gnomad AMR exome AF: 0.00299

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000525

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000866

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00194 AC: 1899 AN: 977759 Hom.: 56 Cov.: 23 AF XY: 0.00167 AC XY: 459 AN XY: 275549

Gnomad4 AFR exome AF: 0.0662

Gnomad4 AMR exome AF: 0.00351

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000388

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000492

Gnomad4 OTH exome AF: 0.00296

GnomAD4 genome AF: 0.0175 AC: 1921 AN: 109892 Hom.: 50 Cov.: 22 AF XY: 0.0145 AC XY: 466 AN XY: 32204

Gnomad4 AFR AF: 0.0593

Gnomad4 AMR AF: 0.0103

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000400

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000153

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00878 Hom.: 42

Bravo AF: 0.0208

ESP6500AA AF: 0.0660 AC: 253

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.00555 AC: 674

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	4.9
DANN	Benign	0.83
DEOGEN2	Benign	0.059	T;.;.;T
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.27	T;T;T;T
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	-0.55	N;N;N;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.39	N;N;N;N
REVEL	Benign	0.049
Sift	Benign	0.74	T;T;T;T
Sift4G	Benign	0.68	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.033
MutPred		0.16		Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);.;
MVP		0.51
MPC		0.59
ClinPred		0.0019	T
GERP RS		-0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs10127175; hg19: chrX-153284172; COSMIC: COSV57653084; COSMIC: COSV57653084;