X-28789325-G-A

Position:

• chrX-28789325-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_014271.4(IL1RAPL1):​c.-19G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (17099 hom., 20472 hem., cov: 23)
  • Exomes 𝑓: 0.52 (99590 hom. 169950 hem.)
  • Failed GnomAD Quality Control
• Consequence: IL1RAPL1 NM_014271.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.755

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant X-28789325-G-A is Benign according to our data. Variant chrX-28789325-G-A is described in ClinVar as [Benign]. Clinvar id is 281021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-28789325-G-A is described in Lovd as [Benign]. Variant chrX-28789325-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL1RAPL1	NM_014271.4	c.-19G>A		5_prime_UTR_variant	2/11	ENST00000378993.6	NP_055086.1
IL1RAPL1	XM_017029240.2	c.-19G>A		5_prime_UTR_variant	2/11		XP_016884729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL1RAPL1	ENST00000378993.6	c.-19G>A		5_prime_UTR_variant	2/11	1	NM_014271.4	ENSP00000368278	P1

Frequencies

GnomAD3 genomes AF: 0.632 AC: 69709 AN: 110355 Hom.: 17086 Cov.: 23 AF XY: 0.627 AC XY: 20430 AN XY: 32589

Gnomad AFR AF: 0.908

Gnomad AMI AF: 0.341

Gnomad AMR AF: 0.598

Gnomad ASJ AF: 0.655

Gnomad EAS AF: 0.847

Gnomad SAS AF: 0.608

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.685

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.629

GnomAD3 exomes AF: 0.585 AC: 105986 AN: 181267 Hom.: 21364 AF XY: 0.574 AC XY: 37857 AN XY: 65911

Gnomad AFR exome AF: 0.916

Gnomad AMR exome AF: 0.616

Gnomad ASJ exome AF: 0.636

Gnomad EAS exome AF: 0.838

Gnomad SAS exome AF: 0.611

Gnomad FIN exome AF: 0.461

Gnomad NFE exome AF: 0.492

Gnomad OTH exome AF: 0.571

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.524 AC: 539644 AN: 1028904 Hom.: 99590 Cov.: 20 AF XY: 0.538 AC XY: 169950 AN XY: 315748

Gnomad4 AFR exome AF: 0.922

Gnomad4 AMR exome AF: 0.614

Gnomad4 ASJ exome AF: 0.637

Gnomad4 EAS exome AF: 0.822

Gnomad4 SAS exome AF: 0.620

Gnomad4 FIN exome AF: 0.450

Gnomad4 NFE exome AF: 0.487

Gnomad4 OTH exome AF: 0.574

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.632 AC: 69766 AN: 110401 Hom.: 17099 Cov.: 23 AF XY: 0.627 AC XY: 20472 AN XY: 32645

Gnomad4 AFR AF: 0.908

Gnomad4 AMR AF: 0.599

Gnomad4 ASJ AF: 0.655

Gnomad4 EAS AF: 0.847

Gnomad4 SAS AF: 0.609

Gnomad4 FIN AF: 0.458

Gnomad4 NFE AF: 0.487

Gnomad4 OTH AF: 0.633

Alfa AF: 0.534 Hom.: 28361

Bravo AF: 0.660

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 11, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Intellectual disability, X-linked 21 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
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	-0.43
CADD	Benign	12
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs6526806; hg19: chrX-28807442;