X-154013049-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001569.4(IRAK1):c.1924G>A(p.Val642Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,208,215 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 46 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., 18 hem., cov: 27)
  • Exomes 𝑓: 0.000093 (0 hom. 28 hem.)
• Consequence: IRAK1 NM_001569.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.92

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006942272).
• BP6: Variant X-154013049-C-T is Benign according to our data. Variant chrX-154013049-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2239348.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High Hemizygotes in GnomAd at 18 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRAK1	NM_001569.4	c.1924G>A	p.Val642Met	missense_variant	12/14	ENST00000369980.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRAK1	ENST00000369980.8	c.1924G>A	p.Val642Met	missense_variant	12/14	1	NM_001569.4	P1

Frequencies

GnomAD3 genomes AF: 0.000651 AC: 74 AN: 113625 Hom.: 0 Cov.: 27 AF XY: 0.000504 AC XY: 18 AN XY: 35743

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000552

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: 0.0000187

Gnomad OTH AF: 0.000650

GnomAD3 exomes AF: 0.000173 AC: 30 AN: 173280 Hom.: 0 AF XY: 0.000111 AC XY: 7 AN XY: 63016

Gnomad AFR exome AF: 0.00208

Gnomad AMR exome AF: 0.0000754

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000635

Gnomad NFE exome AF: 0.0000393

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000932 AC: 102 AN: 1094537 Hom.: 0 Cov.: 32 AF XY: 0.0000774 AC XY: 28 AN XY: 361643

Gnomad4 AFR exome AF: 0.00240

Gnomad4 AMR exome AF: 0.000144

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0000186

Gnomad4 FIN exome AF: 0.0000252

Gnomad4 NFE exome AF: 0.0000285

Gnomad4 OTH exome AF: 0.000153

GnomAD4 genome AF: 0.000651 AC: 74 AN: 113678 Hom.: 0 Cov.: 27 AF XY: 0.000503 AC XY: 18 AN XY: 35806

Gnomad4 AFR AF: 0.00210

Gnomad4 AMR AF: 0.000552

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000187

Gnomad4 OTH AF: 0.000642

Alfa AF: 0.000163 Hom.: 4

Bravo AF: 0.000854

ESP6500AA AF: 0.00163 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000215 AC: 26

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.1924G>A (p.V642M) alteration is located in exon 12 (coding exon 12) of the IRAK1 gene. This alteration results from a G to A substitution at nucleotide position 1924, causing the valine (V) at amino acid position 642 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

IRAK1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 13, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.0020
Dann	Benign	0.73
DEOGEN2	Benign	0.054	T;.;.;T
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.66	T;T;T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.0069	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.26	N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.31	N;N;N;N
REVEL	Benign	0.040
Sift	Benign	0.40	T;T;T;T
Sift4G	Benign	0.27	T;T;T;T
Polyphen		0.027	B;B;B;.
Vest4		0.021
MVP		0.33
MPC		0.49
ClinPred		0.0071	T
GERP RS		-6.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.092

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

Publications

LitVar

Other links and lift over

dbSNP: rs145414165; hg19: chrX-153278500;