rs150439009

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_014271.4(IL1RAPL1):c.784T>G(p.Ser262Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,208,095 control chromosomes in the GnomAD database, including 1 homozygotes. There are 68 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.00014 ( 1 hom. 67 hem. )

Consequence

IL1RAPL1
NM_014271.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.43

Variant links:

Genes affected

IL1RAPL1 (HGNC:5996): (interleukin 1 receptor accessory protein like 1) The protein encoded by this gene is a member of the interleukin 1 receptor family and is similar to the interleukin 1 accessory proteins. This protein has an N-terminal signal peptide, three extracellular immunoglobulin Ig-like domains, a transmembrane domain, an intracellular Toll/IL-1R domain, and a long C-terminal tail which interacts with multiple signalling molecules. This gene is located at a region on chromosome X that is associated with a non-syndromic form of X-linked intellectual disability. Deletions and mutations in this gene were found in patients with intellectual disability. This gene is expressed at a high level in post-natal brain structures involved in the hippocampal memory system, which suggests a specialized role in the physiological processes underlying memory and learning abilities, and plays a role in synapse formation and stabilization. [provided by RefSeq, Jul 2017]

IL1RAPL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04642567).

BP6

Variant X-29917469-T-G is Benign according to our data. Variant chrX-29917469-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 435499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-29917469-T-G is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAdExome at 16 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
IL1RAPL1	NM_014271.4 linkuse as main transcript	c.784T>G	p.Ser262Ala	missense_variant	7/11	ENST00000378993.6
IL1RAPL1	XM_017029240.2 linkuse as main transcript	c.784T>G	p.Ser262Ala	missense_variant	7/11
IL1RAPL1	XM_017029241.2 linkuse as main transcript	c.406T>G	p.Ser136Ala	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL1RAPL1	ENST00000378993.6 linkuse as main transcript	c.784T>G	p.Ser262Ala	missense_variant	7/11	1	NM_014271.4	P1	Q9NZN1-1

Frequencies

GnomAD3 genomes

AF:

0.000160

AC:

AN:

112299

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34427

show subpopulations

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:

0.00420

Gnomad NFE

AF:

0.000319

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000175

AC:

AN:

182778

Hom.:

AF XY:

0.000238

AC XY:

AN XY:

67320

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000366

Gnomad ASJ exome

AF:

0.000536

Gnomad EAS exome

AF:

0.0000723

Gnomad SAS exome

AF:

0.000370

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000196

Gnomad OTH exome

AF:

0.000665

GnomAD4 exome

AF:

0.000142

AC:

156

AN:

1095742

Hom.:

Cov.:

AF XY:

0.000185

AC XY:

AN XY:

361202

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.000517

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.000352

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000137

Gnomad4 OTH exome

AF:

0.000109

GnomAD4 genome

AF:

0.000160

AC:

AN:

112353

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34491

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000319

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000306

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000892

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000439

EpiControl

AF:

0.0000595

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	IL1RAPL1: BS2 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 26, 2016

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

IL1RAPL1-related condition

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 07, 2019

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

0.066

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.57

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.17

T;T

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.61

T;T

M_CAP

Benign

0.069

MetaRNN

Benign

0.046

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.060

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.97

N;.

REVEL

Benign

0.14

Sift

Benign

0.23

T;.

Sift4G

Benign

0.23

T;T

Polyphen

0.0

B;.

Vest4

0.027

MVP

0.53

MPC

0.70

ClinPred

0.022

GERP RS

6.0

Varity_R

0.20

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over