X-28789355-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_014271.4(IL1RAPL1):c.12G>A(p.Pro4=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,206,504 control chromosomes in the GnomAD database, including 6 homozygotes. There are 587 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., 39 hem., cov: 23)
  • Exomes 𝑓: 0.0014 (5 hom. 548 hem.)
• Consequence: IL1RAPL1 NM_014271.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.146

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant X-28789355-G-A is Benign according to our data. Variant chrX-28789355-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 368188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.146 with no splicing effect.
• BS2: High Hemizygotes in GnomAd at 39 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL1RAPL1	NM_014271.4	c.12G>A	p.Pro4=	synonymous_variant	2/11	ENST00000378993.6
IL1RAPL1	XM_017029240.2	c.12G>A	p.Pro4=	synonymous_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL1RAPL1	ENST00000378993.6	c.12G>A	p.Pro4=	synonymous_variant	2/11	1	NM_014271.4	P1

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 140 AN: 111847 Hom.: 1 Cov.: 23 AF XY: 0.00115 AC XY: 39 AN XY: 34023

Gnomad AFR AF: 0.0000649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000953

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000370

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00844

Gnomad NFE AF: 0.00130

Gnomad OTH AF: 0.000662

GnomAD3 exomes AF: 0.00152 AC: 278 AN: 183256 Hom.: 2 AF XY: 0.00165 AC XY: 112 AN XY: 67730

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000730

Gnomad ASJ exome AF: 0.0199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00184

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.00177

GnomAD4 exome AF: 0.00141 AC: 1547 AN: 1094604 Hom.: 5 Cov.: 28 AF XY: 0.00152 AC XY: 548 AN XY: 360198

Gnomad4 AFR exome AF: 0.0000380

Gnomad4 AMR exome AF: 0.000142

Gnomad4 ASJ exome AF: 0.0216

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00196

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.00108

Gnomad4 OTH exome AF: 0.00231

GnomAD4 genome AF: 0.00125 AC: 140 AN: 111900 Hom.: 1 Cov.: 23 AF XY: 0.00114 AC XY: 39 AN XY: 34086

Gnomad4 AFR AF: 0.0000648

Gnomad4 AMR AF: 0.0000952

Gnomad4 ASJ AF: 0.0242

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000371

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00130

Gnomad4 OTH AF: 0.000654

Alfa AF: 0.00324 Hom.: 26

Bravo AF: 0.00124

EpiCase AF: 0.00109

EpiControl AF: 0.00172

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 21, 2023	- -

History of neurodevelopmental disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 28, 2012

This alteration is classified as likely benign based on a combination of the following: 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. -

Intellectual disability, X-linked 21 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	5.1
Dann	Benign	0.75

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: rs143600441; hg19: chrX-28807472; COSMIC: COSV56241025;